bluuebunny/crossref_metadata_2025 huggingface dataset:
Problems of Russian Aggression Investigation against Ukraine
Authors: Shepitko Mykhaylo
Published: February 2023

Current state of investigation of military, war and other crimes caused by Russian aggression against Ukraine is studied, legal and procedural issues of their investigation are outlined. Attention is drawn to the national, foreign and international nature of the investigation of such crimes, which indicates their scale and complexity. Issues that arisen due because of conducting of hostilities on Ukrainian territory and their consequences were also considered (danger of investigative actions, lack of qualified personnel, the existence of a significant number of refugees and temporarily displaced persons, etc.). The purpose of tis research is related to beginning of the unprovoked large-scale war of Russian Federation against Ukraine and the need to bring to criminal responsibility the persons responsible for its resolution, which involves the investigation of war, military and other crimes on the territory of Ukraine and requires the solution of certain urgent problems. Particular attention is paid to Ukrainian unsuccessful attempts to ratify and implement the Rome Statute of the International Criminal Court, which can complicate the assessment of socially dangerous actions in accordance with the Criminal Code of Ukraine and the requirements of the International Criminal Court and hinder the creation of a legal basis for bringing the aggressor to criminal responsibility. In this context, the criminal procedural legislation needs changes that will facilitate the conduct of investigative and judicial actions under martial law conditions, as well as the introduction of electronic justice in Ukraine (in particular, the use of video communication and the provision of information during the transmission and collection of convincing data).
Possibilities of forensic video and audio analysis while investigation of crimes, related to human trafficking
Authors: Brendel Olha , Nikulin Kostiantyn , Aslanovi Elvira
Published: February 2023

This article purpose is to investigate current issues arising while preparation of materials and appointment of forensic video and audio analysis in case of investigations of crimes related to human trafficking, as well as possibilities of analysis for forming the investigation evidence base. Attention is focused on the global and international significance of human trafficking issues, aggravation of people exploitation in war conditions. Exploitation types of victims of human trafficking and responsibility for committing such crimes were analyzed; types of procedural actions are given, for which technical means are used to obtain video and audio information in order to record traces of crimes; main legal characteristics of such procedural actions are specified. Mistakes that subjects of crime investigation make while obtaining evidence that causes loss of a large part of evidence at the stage of the trial, are considered. Specifics and modern possibilities of forensic video and audio analysis for investigation of such crimes are highlighted; it was found out exactly what information from investigated records is used by investigative bodies and for what purpose. An analysis of the tasks solved thanks to video and sound recording expertise and their role in law enforcement activities for further use in court proceedings was carried out. On the basis of researched materials, attention is focused on the results of forensic examinations contributing to resolution of topical issues regarding qualification of acts and circumstances of committed crimes in the field of human trafficking and exploitation of such people, as well as strengthens the evidence base in the case. There are a number of requirements for the proper preparation of materials for forensic video and audio analysis.
МЕМИ ТА МОВА ВОРОЖНЕЧІ: ДЕЯКІ АСПЕКТИ ЦИТУВАННЯ МАС-МЕДІА ДОПИСІВ ОФІЦІЙНИХ ОСІБ У СОЦМЕРЕЖАХ
Authors: СТАРКОВА Ганна
Published: February 2023

Термін «мем» найбільш відомий як позначення певного візуально-текстового переважно розважального контенту, зразок сучасного фольклору. Меми у цьому тлумаченні можуть і слугують елементом пропаганди, але не самостійною «зброєю». Втім найнебезпечніший їхній вплив – формування толерантності до зображуваного – ми завжди недооцінюємо. Наприклад, коли мова йде про поширення мови ворожнечі публічними особами. Недостатня уважність редакцій або цілеспрямована політика засобів масової інформації призводять не лише до ширшої ретрансляції нетолерантних висловів, але й до їх легітимізації. Мета статті – показати, як політики використовують соціальні мережі у власних інтересах і до яких наслідків може призводити їх діяльність. Методологія. У статті проаналізовано деякі приклади, коли впливові особи створювали меми з ознаками іншування або використовували їх для поширення мови ворожнечі. Публікації у соціальних мережах і мас-медіа надають широкий спектр інформації, яка дозволяє дізнаватися причинно-наслідкові зв’язки рішень і подій, підбивати підсумки та узагальнювати підхід до інтерпретації досліджуваних феноменів. Наукова новизна. Колишній президент США Дональд Трамп – яскравий приклад політика, який, маючи колосальну аудиторію у соціальних мережах, вдавався до маніпуляцій та викривлення інформації. Дослідники особливо звертають увагу на нетиповість популярності 45-го президента США та його вплив на електорат, але не порівнюють схожі моделі поведінки публічних осіб у соціальних мережах. Висновки. Аналіз діяльності Трампа та деяких інших політиків, зокрема українських, приводить до наступних висновків: мова ворожнечі існує попри те, помічаємо ми її чи ні. В Україні та інших країнах світу мова ворожнечі присутня у висловлюваннях політиків та громадських діячів, в публікаціях мас-медіа і, звісно, в мемах. Розуміючи та зважуючи потенційні ризики додаткового необережного поширення неперевіреної й упередженої інформації, редакції мас-медіа та професійні спілки зможуть розробити поради для журналістів, спираючись на журналістські стандарти й етику.
Pedagogical practice of teachers
Authors: Silva Patricia Amorim da
Published: February 2023

The article aims to explain about different pedagogical practices and how the education of the educator influences the use of these practices impacting on the student’s learning in a non-formal and/or informal context. The problem to be discussed in it is the dissonance between classroom practice and the theories developed around pedagogical didactics. This work was developed through a qualitative research through the analysis of specific bibliography of the area. The careful reading of several scientific papers and the collection of data from them made it possible to have an idea of the dimension of this dissonance resulting from the lack of communication between practice and theory in the day-to-day classroom and to outline possible measures for the reversal of this picture.
Social entrepreneurship for young people with disabilities: A conceptual analysis
Authors: Ravesangar Kamalesh , Halid Hafinas , Singh Rubee
Published: February 2023

Employment is one of the most basic needs of everyone, including people with disabilities (PWD). However, the numerous obstacles faced by PWD limit their ability to actively participate in the labour market, become economically self-sufficient, and contribute to national economic development. In general, PWD all over the world face a high risk of unemployment. Therefore, this study explored the function of social entrepreneurship in eradicating unemployment among young PWD. This research also emphasised the challenges experienced by PWD in securing employment in Malaysia. Among the issues highlighted are the negative attitudes of employers towards PWD and how employers could adopt the social entrepreneurship perspective. The systematic review method was used to examine the previous literature to accomplish the highlighted purpose and seek answer to the research questions. The literature review revealed problems of unemployment among young PWD. Hence, the improvement of young PWD’s employment have to be focused systematically by taking into account the social entrepreneurship’s perspective. This study is expected to provide a significant contribution to the knowledge on employment of young PWD and would increase the number of their participation in the workplaces.
Implementasi E-Marketing Kelompok Budidaya Trigona Batu Katak
Authors: Yuliana Yayuk , Falahi Adrial , Safina Wan Dian , Harahap Nur’ain
Published: February 2023

Perusahaan kecil dewasa ini dikenal dengan sebuatan industri kreatif merupakan kegiatan ekonomi yang masih terus menerus diperhatikan oleh banyak pihak, karena sektor ini dipandang sebagai sektor yang dapat memberikan kontribusi yang luar biasa bagi negara dalam menangani pengangguran dan pemerataan distribusi pendapatan. Penyebaran virus corona (Covid-19) memukul perekonomian Indonesia, termasuk pelaku usaha. Pemasaran merupakan elemen penting menjalankan sebuah bisnis. Pelaku bisnis yang meluangkan waktunya untuk memikirkan metode pemasaran apa yang tepat agar barang yang dijualnya laku di pasaran karena sukses tidaknya bisnis bergantung pada metode atau cara pemasaran apa dan bagaimana yang dilakukan oleh pelaku usaha khususnya para pelaku UMKM. Minimnya pengetahuan tentang pemasaran secara on line menyebabkan pemasaran terbatas jangkauannya. Pemasaran yang dilakukan usaha Trigona batu katak masih sebatas pemasaran off line. Penelitian ini bertujuan untuk mengkaji dan menganalisis digital marketing di tengah Pandemi Covid 19 sebagai pertahanan ekonomi. Metode penelitian yang dilakukan adalah kualitatif deskriptif. Tujuan dari penelitian deskriptif dengan pendekatan kualitatif adalah untuk memperoleh gambaran implementasi e-marketing pada usaha Trigona Batu Katak. Pengumpulan data dilakukan dengan wawancara dan observasi kepada Ketua Kelompok Budidaya Trigona Batu Katak dan Penyuluh Kehutanan Taman Nasional Gunung Leuser.  Hasil penelitian menunjukkan memanfaatkan digital marketing membantu Usaha Trigona Batu Katak dalam menginformasikan dan berinteraksi secara langsung dengan konsumen yaitu melalui sosial media faccebook dan Wasthsap. Dengan Pemasaran e-marketing diharapkan jangkauan pemasaran semakin luas dan pendapatan masyarakat dusun Batu Katak meningkat seiring ditutupnya ekowisata pada pertengahan maret 2020 akibat pandemi Covid 19.
Immunomodulatory role of oral microbiota in inflammatory diseases and allergic conditions
Authors: Moreno Carlos M. , Boeree Ellie , Freitas Claudia M. Tellez , Weber K. Scott
Published: February 2023

In recent years, the interplay between oral microbiota and systemic disease has gained attention as poor oral health is associated with several pathologies. The oral microbiota plays a role in the maintenance of overall health, and its dysbiosis influences chronic inflammation and the pathogenesis of gum diseases. Periodontitis has also been associated with other diseases and health complications such as cancer, neurogenerative and autoimmune disorders, chronic kidney disease, cardiovascular diseases, rheumatic arthritis, respiratory health, and adverse pregnancy outcomes. The host microbiota can influence immune cell development and immune responses, and recent evidence suggests that changes in oral microbiota composition may also contribute to sensitization and the development of allergic reactions, including asthma and peanut allergies. Conversely, there is also evidence that allergic reactions within the gut may contribute to alterations in oral microbiota composition. Here we review the current evidence of the role of the oral microbiota in inflammatory diseases and health complications, as well as its future relevance in improving health and ameliorating allergic disease.
Detection of selenoprotein transcriptome in chondrocytes of patients with Kashin–Beck disease
Authors: Gong Yi , Wu Yifan , Liu Yanli , Chen Sijie , Zhang Feiyu , Chen Feihong , Wang Chaowei , Li Shujin , Hu Minhan , Huang Ruitian , Xu Ke , Wang Xi , Yang Lei , Ning Yujie , Li Cheng , Zhou Rong , Guo Xiong
Published: February 2023

Background: Kashin–Beck disease (KBD) is a deformed osteochondral disease with a chronic progression that is restrictively distributed in eastern Siberia, North Korea, and some areas of China, and selenium deficiency has been identified as an important factor in the pathogenesis of this disease in recent years.

Objective: The aim of this study is to investigate the selenoprotein transcriptome in chondrocytes and define the contribution of selenoprotein to KBD pathogenesis.

Methods: Three cartilage samples were collected from the lateral tibial plateau of adult KBD patients and normal controls paired by age and sex for real-time quantitative polymerase chain reaction (RT-qPCR) to detect the mRNA expression of 25 selenoprotein genes in chondrocytes. Six other samples were collected from adult KBD patients and normal controls. In addition, immunohistochemistry was used on four adolescent KBD samples and seven normal controls (IHC) to determine the expression of proteins screened by RT-qPCR results that had different gene levels.

Results: Increased mRNA expression of GPX1 and GPX3 was observed in chondrocytes, and stronger positive staining was displayed in the cartilage from both adult and adolescent patients. The mRNA levels of DIO1, DIO2, and DIO3 were increased in KBD chondrocytes; however, the percentage of positive staining decreased in the KBD cartilage of adults.

Conclusion: The selenoprotein transcriptome, mainly the glutathione peroxidase (GPX) and deiodinase (DIO) families were altered in KBD and might play a vital role in the pathogenesis of KBD.
Septins as membrane influencers: direct play or in association with other cytoskeleton partners
Authors: Benoit Béatrice , Poüs Christian , Baillet Anita
Published: February 2023

The cytoskeleton comprises three polymerizing structures that have been studied for a long time, actin microfilaments, microtubules and intermediate filaments, plus more recently investigated dynamic assemblies like septins or the endocytic-sorting complex required for transport (ESCRT) complex. These filament-forming proteins control several cell functions through crosstalks with each other and with membranes. In this review, we report recent works that address how septins bind to membranes, and influence their shaping, organization, properties and functions, either by binding to them directly or indirectly through other cytoskeleton elements.
Artificial intelligence-assisted diagnosis of ocular surface diseases
Authors: Zhang Zuhui , Wang Ying , Zhang Hongzhen , Samusak Arzigul , Rao Huimin , Xiao Chun , Abula Muhetaer , Cao Qixin , Dai Qi
Published: February 2023

With the rapid development of computer technology, the application of artificial intelligence (AI) in ophthalmology research has gained prominence in modern medicine. Artificial intelligence-related research in ophthalmology previously focused on the screening and diagnosis of fundus diseases, particularly diabetic retinopathy, age-related macular degeneration, and glaucoma. Since fundus images are relatively fixed, their standards are easy to unify. Artificial intelligence research related to ocular surface diseases has also increased. The main issue with research on ocular surface diseases is that the images involved are complex, with many modalities. Therefore, this review aims to summarize current artificial intelligence research and technologies used to diagnose ocular surface diseases such as pterygium, keratoconus, infectious keratitis, and dry eye to identify mature artificial intelligence models that are suitable for research of ocular surface diseases and potential algorithms that may be used in the future.
Tamponade and massive pleural effusions secondary to peripherally inserted central catheter in neonates–A complication to be aware of
Authors: Zareef Rana , Anka Mariam , Hatab Taha , El Rassi Issam , Yunis Khalid , Bitar Fadi , Arabi Mariam
Published: February 2023

Background

Peripherally inserted central catheters (PICC) are frequently used in neonatal intensive care units (NICU) to assist premature and critically ill neonates. Massive pleural effusions, pericardial effusions, and cardiac tamponade secondary to PICC are extremely uncommon but have potentially fatal consequences.

Objective

This study investigates the incidence of tamponade, large pleural, and pericardial effusions secondary to peripherally inserted central catheters in a neonatal intensive care unit at a tertiary care center over a 10-year period. It explores possible etiologies behind such complications and suggests preventative measures.

Study design

Retrospective analysis of neonates who were admitted to the NICU at the AUBMC between January 2010 and January 2020, and who required insertion of PICC. Neonates who developed tamponade, large pleural, or pericardial effusions secondary to PICC insertion were investigated.

Results

Four neonates developed significant life-threatening effusions. Urgent pericardiocentesis and chest tube placement were required in two and one patients, respectively. No fatalities were encountered.

Conclusion

The abrupt onset of hemodynamic instability without an obvious cause in any neonate with PICC in situ should raise suspicion of pleural or pericardial effusions. Timely diagnosis through bedside ultrasound, and prompt aggressive intervention are critical.
Differences in protein expression, at the basal state and at 2 h of insulin infusion, in muscle biopsies from healthy Arab men with high or low insulin sensitivity measured by hyperinsulinemic euglycemic clamp
Authors: Bettahi Ilham , Krishnankutty Roopesh , Jaganjac Morana , Suleiman Noor Nabeel M. , Ramanjaneya Manjunath , Jerobin Jayakumar , Hassoun Shaimaa , Alkasem Meis , Abdelhakam Ibrahem , Iskandarani Ahmad , Samra Tareq A. , Mohamed-Ali Vidya , Abou-Samra Abdul Badi
Published: February 2023

Background

Skeletal muscle is the main site for insulin-dependent glucose disposal. The hyperinsulinemic euglycemic clamp (HIEC) is the gold standard for the assessment of insulin sensitivity (IS). We have previously shown that insulin sensitivity, measured by HIEC, varied widely among a group of 60 young healthy men with normoglycemia. The aim of this study was to correlate the proteomic profile of skeletal muscles to insulin sensitivity.

Methods

Muscle biopsies from 16 subjects having the highest (M ≥ 13; n = 8, HIS) and lowest (M ¾ 6, n = 8, LIS) IS were obtained at baseline and during insulin infusion after stabilization of the blood glucose level and glucose infusion rate at the end of the HIEC. The samples were processed using a quantitative proteomic analysis approach.

Results

At baseline, 924 proteins were identified in the HIS and LIS groups. Among the 924 proteins detected in both groups, three were suppressed and three were increased significantly in the LIS subjects compared with the HIS subjects. Following insulin infusion, 835 proteins were detected in both groups. Among the 835 proteins, two showed differential responsiveness to insulin; ATP5F1 protein was decreased, and MYLK2 was higher in the LIS group compared with that in the HIS group. Our data suggest that alteration in mitochondrial proteins and an increased number of proteins involved in fast-twitch fiber correlate to insulin sensitivity in healthy young Arab men.

Conclusions

These results suggest a change in a small number of differentially expressed proteins. A possible reason for this small change could be our study cohorts representing a homogeneous and healthy population. Additionally, we show differences in protein levels from skeletal muscle in low and high insulin sensitivity groups. Therefore, these differences may represent early events for the development of insulin resistance, pre-diabetes, and type 2 diabetes.
Oxidative stress in cerebrovascular disease and associated diseases
Authors: Kumar Vijay , Bishayee Kausik , Park Soochul , Lee Unjoo , Kim Jaebong
Published: February 2023

Cellular aging is the most severe risk factor for neurodegenerative disease. Simultaneously, oxidative stress (OS) is a critical factor in the aging process, resulting from an imbalance between reactive oxygen and nitrogen species and the antioxidant defense system. Emerging evidence indicates that OS is a common cause of several age-related brain pathologies, including cerebrovascular diseases. Elevated OS disrupts endothelial functional ability by diminishing the bioavailability of nitric oxide (a vascular dilator), induces atherosclerosis, and impairs vasculature, which are all common characteristics of cerebrovascular disease. In this review, we summarize evidence supporting an active role of OS in cerebrovascular disease progression, focusing primarily on stroke pathogenesis. We briefly discuss hypertension, diabetes, heart disease, and genetic factors that are often linked to OS and are considered associated factors influencing stroke pathology. Finally, we discuss the current pharmaceutics/therapeutics available for treating several cerebrovascular diseases.
Regular physical activity moderates the adverse impact of type 2 diabetes on brain atrophy independently from HbA1c
Authors: Moreno Carolina , d’Almeida Otília C. , Gomes Leonor , Paiva Isabel , Castelo-Branco Miguel
Published: February 2023

Objective

Brain atrophy has been consistently associated with type 2 diabetes, beginning in early stages of dysglycemia, independently from micro and macrovascular complications. On the contrary, physical activity relates with larger brain volumes. Our aim is to assess the influence of regular physical activity on brain volumes in people with type 2 diabetes.

Methods

A cross-sectional multimodal evaluation with 3T MRI was performed on 170 individuals: 85 individuals with type 2 diabetes and 85 controls. They underwent clinical examination, blood sampling and 3T MRI. Brain volumes (mm3) were estimated using FreeSurfer 7. Physical activity duration was self-reported by the participants as the number of hours of physical activity per week for at least the previous 6 months. Statistical analysis was performed with IBM SPSS 27.

Results

People with type 2 diabetes had significantly lower cortical and subcortical volumes, adjusted for age and individual intracranial volume, comparing to controls. Regression analysis showed that within type 2 diabetes group, lower gray matter volumes were associated with lesser physical activity duration (hours/week), independently from HbA1c. Moreover, there were significant moderate positive correlations between regular physical activity duration and gray matter volumes of cortical and subcortical subregions, specifically in the diabetes group.

Conclusions

This study reveals a putative beneficial effect of regular physical activity independently of glycemic control, as assessed by HbA1c, which might contribute to reduce the negative impact of type 2 diabetes in the brain.
Exosomal RNAs in the development and treatment of pituitary adenomas
Authors: Chang Mengqi , Jiang Shenzhong , Guo Xiaopeng , Gao Jun , Liu Peng , Bao Xinjie , Feng Ming , Wang Renzhi
Published: February 2023

Exosomes are small extracellular vesicles that carry various bioactive molecules including various RNAs that modulate the activities of recipient cells. It has drawn considerable attention as means of cell communication and drug delivery. Exosome plays important role in various tumors, but it is rarely summarized in pituitary adenoma (PA). PA is the second most common primary central nervous system tumor, and its recurrence and persistent postoperative hormone hypersecretion lead to compromised quality of life. How exactly exosomes impact tumor development and hormone secretion is important for the development of this tumor diagnosis and treatment. In this review, we discuss how exosomal RNAs impact PAs and their potential as future clinical therapies. In our literature review, first, we found that exosomal microRNA hsa-miR-1180-3p is a potential early biomarker for NFPAs. Since NFPAs are typically difficult to diagnose, this is an especially important finding. Second, exosomal protein transcripts are potential invasive biomarker, such as MMP1, N-cadherin, CDK6, RHOU, INSM1, and RASSF10. Third, exosomal contents such as hsa-miR-21-5p promote distant bone formation of GHPA patients. Fourth, tumor suppressors in the exosome constitute novel therapeutic application of exosome, including long noncoding RNA (lncRNA) H19, miR-149-5p, miR-99a-3p, and miR-423-5p. This review discusses the possible mechanisms of exosome and their contents in PA and promotes the use of exosomes in both clinical diagnosis and treatment of this tumor.
Performance evaluation and modeling of active tile in raised-floor data centers: An empirical study on the single tile case
Authors: Gao Haoyu , Yue Qiuling , Kou Yuqing , Wan Jianxiong , Li Leixiao , Fu Lijun
Published: February 2023

Raised-floor data centers usually suffer from the local hotspots resulted from uneven cool air delivery. These hotspots not only degrade server performance, but also threat equipment reliability. The commonly used industrial practice of increasing the Computer Room Air Conditioner (CRAC) blower speed for removing hotspots is energy inefficient and may lead to overcooling of some servers. In this paper, we explore the potential of active tiles in data center cooling management. In particular, we deploy a prototype of active tile in a production data center and conduct extensive experiments to investigate the cooling performance. It is shown that deploying the active tiles with even 10% fan speed increases the tile flow by 49%, and sealing the under-rack gap reduces the rack bottom temperature by up to 6°C. Moreover, three machine learning techniques, i.e., Gaussian Process Regression (GPR), Artificial Neural Network (ANN), and Multivariate Linear Regression (MLR) are employed to construct end-to-end data-driven thermal models for the active tile. Using field measured data as training and testing data sets, it is concluded that GPR and ANN are competent for accurate thermal modeling of active tiles. Specifically, GPR achieves the smallest prediction error which is around 0.3°C.
The nature of corporate social responsibility disclosure and investment efficiency: Evidence from China
Authors: Huang Fangliang , Chen Meng , Liu Rongbing
Published: February 2023

Corporate social responsibility (CSR) disclosure has gained more attention from both practitioners and scholars. Company executives are starting to seek competitive differentiation from their sustainability strategies (McKinsey & Company, 2020). This study explores the link between CSR disclosure and investment efficiency using a sample of Chinese-listed firms from 2010 to 2019. The findings suggest that CSR disclosure improves investment efficiency through reducing information asymmetry and agency cost. Also, mandatory CSR disclosure has a more significant effect on investment efficiency than voluntary CSR disclosure. In addition, this study finds that the nature of ownership (state-owned vs. non-state-owned), CSR performance, institutional ownership, and the level of industry competition all affect this relationship. The study provides meaningful implications for future CSR disclosure policy development.
Network attention and carbon dioxide emission performance of agricultural enterprises: Empirical evidence from China’s baidu search index
Authors: Chen Jiancheng , Sun Heng
Published: February 2023

Based on the network attention data of China’s agricultural listed companies from 2012 to 2020, this paper uses the IV model to measure and investigate the impact of network attention on the carbon dioxide emission performance of China’s agricultural listed companies and its mechanism. The findings are as follows: 1) The carbon dioxide emission intensity of listed agricultural companies in China is generally decreasing year by year and the carbon dioxide emission performance is improving; 2) The increasing network attention has significantly reduced the carbon dioxide emission intensity of agricultural listed companies and brought about better carbon dioxide emission performance; 3) The relationship between network attention and carbon dioxide emission performance of agricultural listed companies has network, regional and property heterogeneity; 4) The investment in environmental protection has strengthened the inhibition effect of network attention on the unit carbon dioxide emissions of agricultural listed companies. The research conclusion enriches the literature on “network concern - environmental governance”, and also provides ideas for developing countries to exert the environmental governance effect of network concern in the process of carbon neutrality.
Microsatellite instability-related prognostic risk score (MSI-pRS) defines a subset of lung squamous cell carcinoma (LUSC) patients with genomic instability and poor clinical outcome
Authors: Hu Zixin , Liu Zhening , Zheng Jiabin , Peng Yanmei , Lu Xingyu , Li Jia , Tan Kexin , Cui Huijuan
Published: February 2023

Background: Lung squamous cell carcinoma (LUSC) shares less typical onco-drivers and target resistance, but a high overall mutation rate and marked genomic complexity. Mismatch repair (MMR) deficiency leads to microsatellite instability (MSI) and genomic instability. MSI is not an ideal option for prognosis of LUSC, whereas its function deserves exploration.

Method: MSI status was classified by MMR proteins using unsupervised clustering in the TCGA–LUSC dataset. The MSI score of each sample was determined by gene set variation analysis. Intersections of the differential expression genes and differential methylation probes were classified into functional modules by weighted gene co-expression network analysis. Least absolute shrinkage and selection operator regression and stepwise gene selection were performed for model downscaling.

Results: Compared with the MSI-low (MSI-L) phenotype, MSI-high (MSI-H) displayed higher genomic instability. The MSI score was decreased from MSI-H to normal samples (MSI-H > MSI-L > normal). A total of 843 genes activated by hypomethylation and 430 genes silenced by hypermethylation in MSI-H tumors were classified into six functional modules. CCDC68, LYSMD1, RPS7, and CDK20 were used to construct MSI-related prognostic risk score (MSI-pRS). Low MSI-pRS was a protective prognostic factor in all cohorts (HR = 0.46, 0.47, 0.37; p-value = 7.57e-06, 0.009, 0.021). The model contains tumor stage, age, and MSI-pRS that showed good discrimination and calibration. Decision curve analyses indicated that microsatellite instability-related prognostic risk score added extra value to the prognosis. A low MSI-pRS was negatively correlated with genomic instability. LUSC with low MSI-pRS was associated with increased genomic instability and cold immunophenotype.

Conclusion: MSI-pRS is a promising prognostic biomarker in LUSC as the substitute of MSI. Moreover, we first declared that LYSMD1 contributed to genomic instability of LUSC. Our findings provided new insights in the biomarker finder of LUSC.
Destin2: Integrative and cross-modality analysis of single-cell chromatin accessibility data
Authors: Guan Peter Y. , Lee Jin Seok , Wang Lihao , Lin Kevin Z. , Mei Wenwen , Chen Li , Jiang Yuchao
Published: February 2023

We propose Destin2, a novel statistical and computational method for cross-modality dimension reduction, clustering, and trajectory reconstruction for single-cell ATAC-seq data. The framework integrates cellular-level epigenomic profiles from peak accessibility, motif deviation score, and pseudo-gene activity and learns a shared manifold using the multimodal input, followed by clustering and/or trajectory inference. We apply Destin2 to real scATAC-seq datasets with both discretized cell types and transient cell states and carry out benchmarking studies against existing methods based on unimodal analyses. Using cell-type labels transferred with high confidence from unmatched single-cell RNA sequencing data, we adopt four performance assessment metrics and demonstrate how Destin2 corroborates and improves upon existing methods. Using single-cell RNA and ATAC multiomic data, we further exemplify how Destin2’s cross-modality integrative analyses preserve true cell-cell similarities using the matched cell pairs as ground truths. Destin2 is compiled as a freely available R package available at https://github.com/yuchaojiang/Destin2.
Identifying hepatic genes regulating the ovine response to gastrointestinal nematodes using RNA-Sequencing
Authors: Dixon Samantha , Karrow Niel A. , Borkowski Emma , Suarez-Vega Aroa , Menzies Paula I. , Kennedy Delma , Peregrine Andrew S. , Mallard Bonnie A. , Cánovas Ángela
Published: February 2023

Gastrointestinal nematode (GIN) infections are considered the most important disease of grazing sheep and due to increasing anthelmintic resistance, chemical control alone is inadequate. Resistance to Gastrointestinal nematode infection is a heritable trait, and through natural selection many sheep breeds have higher resistance. Studying the transcriptome from GIN-exposed and GIN-unexposed sheep using RNA-Sequencing technology can provide measurements of transcript levels associated with the host response to Gastrointestinal nematode infection, and these transcripts may harbor genetic markers that can be used in selective breeding programs to enhance disease resistance. The objective of this study was to compare liver transcriptomes of sheep naturally exposed to Gastrointestinal nematode s, with either high or low parasite burdens, to GIN-unexposed control sheep in order to identify key regulator genes and biological processes associated with Gastrointestinal nematode infection. Differential gene expression analysis revealed no significant differentially expressed genes (DEG) between sheep with a high or low parasite burden (p-value ≤0.01; False Discovery Rate (FDR) ≤ 0.05; and Fold-Change (FC) of > ±2). However, when compared to the control group, low parasite burden sheep showed 146 differentially expressed genes (64 upregulated and 82 downregulated in the low parasite burden group relative to the control), and high parasite burden sheep showed 159 differentially expressed genes (57 upregulated and 102 downregulated in the low parasite burden group relative to the control) (p-value ≤0.01; FDR ≤0.05; and FC of > ±2). Among these two lists of significant differentially expressed genes, 86 differentially expressed genes (34 upregulated, 52 downregulated in the parasited group relative to the control) were found in common between the two parasite burden groups compared to the control (GIN-unexposed sheep). Functional analysis of these significant 86 differentially expressed genes found upregulated genes involved in immune response and downregulated genes involved in lipid metabolism. Results of this study offer insight into the liver transcriptome during natural Gastrointestinal nematode exposure that helps provide a better understanding of the key regulator genes involved in Gastrointestinal nematode infection in sheep.
Therapeutic equine hyperimmune antibodies with high and broad-spectrum neutralizing activity protect rodents against SARS-CoV-2 infection
Authors: Li Entao , Han Qiuxue , Bi Jinhao , Wei Shimeng , Wang Shen , Zhang Ying , Liu Jun , Feng Na , Wang Tiecheng , Wu Jun , Yang Songtao , Zhao Yongkun , Liu Bo , Yan Feihu , Xia Xianzhu
Published: February 2023

The emergence of SARS-CoV-2 variants stresses the continued need for broad-spectrum therapeutic antibodies. Several therapeutic monoclonal antibodies or cocktails have been introduced for clinical use. However, unremitting emerging SARS-CoV-2 variants showed reduced neutralizing efficacy by vaccine induced polyclonal antibodies or therapeutic monoclonal antibodies. In our study, polyclonal antibodies and F(ab’)2 fragments with strong affinity produced after equine immunization with RBD proteins produced strong affinity. Notably, specific equine IgG and F(ab’)2 have broad and high neutralizing activity against parental virus, all SARS-CoV-2 variants of concern (VOCs), including B.1.1,7, B.1.351, B.1.617.2, P.1, B.1.1.529 and BA.2, and all variants of interest (VOIs) including B.1.429, P.2, B.1.525, P.3, B.1.526, B.1.617.1, C.37 and B.1.621. Although some variants weaken the neutralizing ability of equine IgG and F(ab’)2 fragments, they still exhibited superior neutralization ability against mutants compared to some reported monoclonal antibodies. Furthermore, we tested the pre-exposure and post-exposure protective efficacy of the equine immunoglobulin IgG and F(ab’)2 fragments in lethal mouse and susceptible golden hamster models. Equine immunoglobulin IgG and F(ab’)2 fragments effectively neutralized SARS-CoV-2 in vitro, fully protected BALB/c mice from the lethal challenge, and reduced golden hamster’s lung pathological change. Therefore, equine pAbs are an adequate, broad coverage, affordable and scalable potential clinical immunotherapy for COVID-19, particularly for SARS-CoV-2 VOCs or VOIs.
Targeting matrix metalloproteases in diabetic wound healing
Authors: Chen Junren , Qin Siqi , Liu Shengmeng , Zhong Kexin , Jing Yiqi , Wu Xuan , Peng Fu , Li Dan , Peng Cheng
Published: February 2023

Chronic inflammation participates in the progression of multiple chronic diseases, including obesity, diabetes mellitus (DM), and DM related complications. Diabetic ulcer, characterized by chronic wounds that are recalcitrant to healing, is a serious complication of DM tremendously affecting the quality of life of patients and imposing a costly medical burden on society. Matrix metalloproteases (MMPs) are a family of zinc endopeptidases with the capacity of degrading all the components of the extracellular matrix, which play a pivotal part in healing process under various conditions including DM. During diabetic wound healing, the dynamic changes of MMPs in the serum, skin tissues, and wound fluid of patients are in connection with the degree of wound recovery, suggesting that MMPs can function as essential biomarkers for the diagnosis of diabetic ulcer. MMPs participate in various biological processes relevant to diabetic ulcer, such as ECM secretion, granulation tissue configuration, angiogenesis, collagen growth, re-epithelization, inflammatory response, as well as oxidative stress, thus, seeking and developing agents targeting MMPs has emerged as a potential way to treat diabetic ulcer. Natural products especially flavonoids, polysaccharides, alkaloids, polypeptides, and estrogens extracted from herbs, vegetables, as well as animals that have been extensively illustrated to treat diabetic ulcer through targeting MMPs-mediated signaling pathways, are discussed in this review and may contribute to the development of functional foods or drug candidates for diabetic ulcer therapy. This review highlights the regulation of MMPs in diabetic wound healing, and the potential therapeutic ability of natural products for diabetic wound healing by targeting MMPs.
PHLDA1 modulates microglial response and NLRP3 inflammasome signaling following experimental subarachnoid hemorrhage
Authors: Lai Jinqing , Chen Genwang , Wu Zhe , Yu Shaoyang , Huang Rongfu , Zeng Yile , Lin Weibin , Fan Chunmei , Chen Xiangrong
Published: February 2023

Balancing microglia M1/M2 polarization is an effective therapeutic strategy for neuroinflammation after subarachnoid hemorrhage (SAH). Pleckstrin homology-like domain family A member 1 (PHLDA1) has been demonstrated to play a crucial role in immune response. However, the function roles of PHLDA1 in neuroinflammation and microglial polarization after SAH remain unclear. In this study, SAH mouse models were assigned to treat with scramble or PHLDA1 small interfering RNAs (siRNAs). We observed that PHLDA1 was significantly increased and mainly distributed in microglia after SAH. Concomitant with PHLDA1 activation, nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome expression in microglia was also evidently enhanced after SAH. In addition, PHLDA1 siRNA treatment significantly reduced microglia-mediated neuroinflammation by inhibiting M1 microglia and promoting M2 microglia polarization. Meanwhile, PHLDA1 deficiency reduced neuronal apoptosis and improved neurological outcomes after SAH. Further investigation revealed that PHLDA1 blockade suppressed the NLRP3 inflammasome signaling after SAH. In contrast, NLRP3 inflammasome activator nigericin abated the beneficial effects of PHLDA1 deficiency against SAH by promoting microglial polarization to M1 phenotype. In all, we proposed that PHLDA1 blockade might ameliorate SAH-induced brain injury by balancing microglia M1/M2 polarization via suppression of NLRP3 inflammasome signaling. Targeting PHLDA1 might be a feasible strategy for treating SAH.
The protein kinase R modifies gut physiology to limit colitis
Authors: Yim Howard Chi Ho , Chakrabarti Arindam , Kessler Sean , Morimoto Hiroyuki , Wang Die , Sooraj Dhanya , Ahmed Afsar U. , de la Motte Carol , Silverman Robert H. , Williams Bryan RG. , Sadler Anthony J.
Published: February 2023

Here we investigate the function of the innate immune molecule protein kinase R (PKR) in intestinal inflammation. To model a colitogenic role of PKR, we determine the physiological response to dextran sulfate sodium (DSS) of wild-type and two transgenic mice strains mutated to express either a kinase-dead PKR or to ablate expression of the kinase. These experiments recognize kinase-dependent and -independent protection from DSS-induced weight loss and inflammation, against a kinase-dependent increase in the susceptibility to DSS-induced injury. We propose these effects arise through PKR-dependent alteration of gut physiology, evidenced as altered goblet cell function and changes to the gut microbiota at homeostasis that suppresses inflammasome activity by controlling autophagy. These findings establish that PKR functions as both a protein kinase and a signaling molecule in instituting immune homeostasis in the gut.
Prediction of early treatment response to the combination therapy of TACE plus lenvatinib and anti-PD-1 antibody immunotherapy for unresectable hepatocellular carcinoma: Multicenter retrospective study
Authors: Li Shuqun , Wu Junyi , Wu Jiayi , Fu Yangkai , Zeng Zhenxin , Li Yinan , Li Han , Liao Weijia , Yan Maolin
Published: February 2023

Background and aim

The purpose of this study was to investigate and validate the efficacy of a nomogram model in predicting early objective response rate (ORR) in u-HCC patients receiving a combination of TACE, Lenvatinib, and anti-PD-1 antibody treatment after 3 months (triple therapy).

Method

This study included 169 u-HCC cases from five different hospitals. As training cohorts (n = 102), cases from two major centers were used, and external validation cohorts (n = 67) were drawn from the other three centers. The clinical data and contrast-enhanced MRI characteristics of patients were included in this retrospective study. For evaluating MRI treatment responses, the modified revaluation criteria in solid tumors (mRECIST) were used. Univariate and multivariate logistic regression analyses were used to select relevant variables and develop a nomogram model. Our as-constructed nomogram was highly consistent and clinically useful, as confirmed by the calibration curve and decision curve analysis (DCA); an independent external cohort also calibrated the nomogram.

Results

The ORR was 60.9% and the risk of early ORR was independently predicted by AFP, portal vein tumor thrombus (PVTT), tumor number, and size in both the training (C-index = 0.853) and test (C-index = 0.800) cohorts. The calibration curve revealed that the nomogram-predicted values were consistent with the actual response rates in both cohorts. Furthermore, DCA indicated that our developed nomogram performed well in clinical settings.

Conclusion

The nomogram model accurately predicts early ORR achieved by triple therapy in u-HCC patients, which aids in individual decision-making and modifying additional therapies for u-HCC cases.
The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy
Authors: Hasankhani Aliakbar , Bahrami Abolfazl , Tavakoli-Far Bahareh , Iranshahi Setare , Ghaemi Farnaz , Akbarizadeh Majid Reza , Amin Ali H. , Abedi Kiasari Bahman , Mohammadzadeh Shabestari Alireza
Published: February 2023

Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the lower and upper respiratory tract in humans. SARS-CoV-2 infection is associated with the induction of a cascade of uncontrolled inflammatory responses in the host, ultimately leading to hyperinflammation or cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2 immunopathogenesis, directly related to the severity of the disease and mortality in COVID-19 patients. Considering the lack of any definitive treatment for COVID-19, targeting key inflammatory factors to regulate the inflammatory response in COVID-19 patients could be a fundamental step to developing effective therapeutic strategies against SARS-CoV-2 infection. Currently, in addition to well-defined metabolic actions, especially lipid metabolism and glucose utilization, there is growing evidence of a central role of the ligand-dependent nuclear receptors and peroxisome proliferator-activated receptors (PPARs) including PPARα, PPARβ/δ, and PPARγ in the control of inflammatory signals in various human inflammatory diseases. This makes them attractive targets for developing therapeutic approaches to control/suppress the hyperinflammatory response in patients with severe COVID-19. In this review, we (1) investigate the anti-inflammatory mechanisms mediated by PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the recent literature, highlight the importance of PPAR subtypes for the development of promising therapeutic approaches against the cytokine storm in severe COVID-19 patients.
An integrated co-expression network analysis reveals novel genetic biomarkers for immune cell infiltration in chronic kidney disease
Authors: Xia Jia , Hou Yutong , Cai Anxiang , Xu Yingjie , Yang Wen , Huang Masha , Mou Shan
Published: February 2023

Background

Chronic kidney disease (CKD) is characterized by persistent damage to kidney function or structure. Progression to end-stage leads to adverse effects on multiple systems. However, owing to its complex etiology and long-term cause, the molecular basis of CKD is not completely known.

Methods

To dissect the potential important molecules during the progression, based on CKD databases from Gene Expression Omnibus, we used weighted gene co-expression network analysis (WGCNA) to identify the key genes in kidney tissues and peripheral blood mononuclear cells (PBMC). Correlation analysis of these genes with clinical relevance was evaluated based on Nephroseq. Combined with a validation cohort and receiver operating characteristic curve (ROC), we found the candidate biomarkers. The immune cell infiltration of these biomarkers was evaluated. The expression of these biomarkers was further detected in folic acid-induced nephropathy (FAN) murine model and immunohistochemical staining.

Results

In total, eight genes (CDCP1, CORO1C, DACH1, GSTA4, MAFB, TCF21, TGFBR3, and TGIF1) in kidney tissue and six genes (DDX17, KLF11, MAN1C1, POLR2K, ST14, and TRIM66) in PBMC were screened from co-expression network. Correlation analysis of these genes with serum creatinine levels and estimated glomerular filtration rate from Nephroseq showed a well clinical relevance. Validation cohort and ROC identified TCF21, DACH1 in kidney tissue and DDX17 in PBMC as biomarkers for the progression of CKD. Immune cell infiltration analysis revealed that DACH1 and TCF21 were correlated with eosinophil, activated CD8 T cell, activated CD4 T cell, while the DDX17 was correlated with neutrophil, type-2 T helper cell, type-1 T helper cell, mast cell, etc. FAN murine model and immunohistochemical staining confirmed that these three molecules can be used as genetic biomarkers to distinguish CKD patients from healthy people. Moreover, the increase of TCF21 in kidney tubules might play important role in the CKD progression.

Discussion

We identified three promising genetic biomarkers which could play important roles in the progression of CKD.