bluuebunny/crossref_metadata_2025 huggingface dataset:
Massive Philanthropy as Marketing Competition in The New Normal Era During Pandemic
Authors: Nizar Muhammad , Chabibi Muhammad
Published: April 2022

This paper explains the philanthropic phenomenon that occurred in Indonesian people, especially the people of Cirebon City when the transmission of the covid-19 virus reached it’s peak again in November 2020. Basically, the philanthropic movement in the Covid-19 pandemic era emerged based on chaotic humanitarian attention and the uncertain economic stability of the country. This provides a stimulus to philanthropic activists to participate in social-humanitarian concerns and social-economic restoration. This type of research is qualitative with interview methods and online media documentation. This study concludes that the philanthropic movement should be based on humanitarian solidarity and religious normativity. However, several philanthropic activists in Cirebon City have used the opportunity of the COVID-19 pandemic moment as a personal economic recovery by using accurate marketing management wrapped in social philanthropy. This is a new motive that combines the humanitarian philanthropy movement with a marketing work system when COVID-19 as a natural disaster strikes with the aim of helping people as well as marketing their commodity products. The reason is that the demands for economic improvement during a pandemic require philanthropic activists to give and share as well as sell and promote.
Attitude and Perceived Social Norms Towards Risk-taking Behaviors among Male University Students in Malaysia
Authors: Zulkifli Sarah Mashitah , Sehu Mohamad Zhooriyati , Lee Sook Huey
Published: April 2022

This study was conducted to investigate the attitudes and perceived social norms regarding risk behaviours as well as to ascertain how social context influences their likelihood to adhere to perceived social norms. The study adopted a qualitative methodology with a phenomenological design. The study applied purposive and snowballing sampling methods, and in-depth interviews were conducted among six participants. Findings indicated that students' attitudes towards risk-taking behaviours were mainly positive due to the perception that they knew their limits and were able to restrain their use for social and recreational purposes. Those with negative attitudes had negative experiences due to obsessive engagement in the behaviour. This study suggests the importance of having an open discussion surrounding risk-taking behaviours and the need to educate university students and understand the thought process regarding their attitudes towards risk-taking behaviours.
Self-Efficacy in Learning Mathematics Online
Authors: Julaihi Nor Hazizah , Zainuddin Puteri Faida Alya , Che Md Nor Rumaizah , Ahmad Bakri Syah Runniza , Hamdan Anniza , Salleh Juliza , Bujang Noriham
Published: April 2022

Online learning has been a need for worldwide education systems due to Covid-19. It is essential to study the students' self-efficacy to determine online learning success. Research suggests that self-efficacy can boost student achievement, foster emotional health and well-being, and be a valid predictor of motivation and learning. The purpose of this paper is to examine the students' self-efficacy in Mathematics online learning using a reliable instrument adapted from the "Learning Self-Efficacy Scale (OLSES)" developed by Zimmerman and Kulikowich in 2016. The respondents consisted of 343 undergraduate students in Sarawak, Malaysia. This study's quantitative data analysis methods include descriptive and inferential statistics. The analysis reported that most of the respondents had moderate to high levels of self-efficacy, whereas most of them were comfortable with Mathematics online learning. Specifically, there was a significant relationship between students' self-efficacy and the domains, namely learning in an online environment, time management, and technology use. This study also found no significant difference in the mean scores of students' self-efficacy concerning gender, academic performance, and online learning prior experience. However, there was a significant difference in mean scores for students' self-efficacy across their online learning comfort levels. Further analysis indicated that students who were notably comfortable projected a significantly higher self-efficacy than those with an average or low comfort level. Although the students in this study mostly had moderate to high levels of self-efficacy, there is still room to improve and strengthen their self-efficacy, especially in their abilities and readiness to engage in online learning and thus in achieving good academic performance.
Percentile Norms for an Early Reading Assessment in Malay
Authors: LEE JULIA A C , Lee Seung-Jin , Ong Puay Hoon , Nordin Zaimuariffudin Shukri , Mat Yusoff Nur Fatihah
Published: April 2022

The study aimed to develop percentile norms on early reading proficiency among young elementary school children. These percentile norms were derived from a suite of early reading assessments in Malay administered to 866 Primary One (Grade 1 equivalent) school children from multilingual and multi-ethnic backgrounds. During testing, the children (462 males and 404 females) were approximately seven years old. The early reading assessment battery included measures such as letter writing, letter name knowledge, letter name fluency, rapid automatised naming, phonological awareness comprising elision, phonological memory, spelling, word reading accuracy, word reading efficiency, oral reading fluency, reading comprehension, vocabulary comprising expressive vocabulary and receptive vocabulary, and listening comprehension. These percentile norms are useful for the early identification and intervention of young children with reading difficulties and reading disabilities from multilingual communities whose languages include Malay, a transparent orthography. The implications of using the norms data for the diagnosis and classification of children with reading difficulties are discussed.
Students' Perceptions of Online Learning Experiences for ESL Speaking Activities
Authors: Nik Fauzi Sheela Faizura Binti , Ambi Siti Hafizah , Abang Madaud Abang  Fhaeizdhyall , Unin Norseha
Published: April 2022

Performing speaking tasks via online learning can be challenging for first-year university students. This quantitative study explored the students' perceptions of online learning experiences, challenges, and strategies in implementing English speaking activities. 127 out of 315 students responded to the questionnaire, which involved asking for information on students' backgrounds, perceptions of online platforms, online learning adoption and difficulties in implementing speaking tasks via online learning. The findings reveal that while most students have positive perceptions of online learning platforms for English-speaking tasks, a small percentage of them still prefer physical classroom learning. Nevertheless, lecturers' strategies of prompting for ideas, asking questions, and exploring creative ideas for speaking activities have successfully met the students' online learning needs.
KAJI EKSPERIMEN MASSA REFERIGERANT TERHADAP OPTIMALISASI FUNGSI AC PADA KENDARAAN INOVA DIESEL 2008
Authors: Farida Nike Nur , Yahya Wachid , Mukarramah Khaeratul
Published: April 2022

One of the functions of the vehicle air conditioner is to provide thermal comfort in the cabin space. Thermal Comfort can provide benefits such as reducing driver fatigue and increasing driving efficiency and safety, so it is important that the temperature of the vehicle is in accordance with human thermal comfort (22.8-26oC). The purpose of this study was to see how much volume and pressure the car air conditioner had in order to get optimal thermal comfort by varying the volume of the refrigerant in the air conditioner and recording the pressure, temperature in the condenser, evaporator and cabin space. The test equipment in this study was a 2008 Toyota Innova Diesel with refrigerant R 134a with a volume variation of 600 grams, 700 grams, 800 grams, 900 grams, 1000 grams and 1,100 grams. The results showed that the more refrigerant volume will make the low pressure and high pressure in the AC system rise. Optimal low pressure (1.5 bar) and optimal high pressure (15.1 bar) were obtained at a refrigerant volume of 700 grams. The relationship between the refrigerant mass and the temperature in the evaporator line has a tendency if the volume of refrigerant plus the temperature in the evaporator line and the cabin will decrease to a certain point the temperature will tend to rise. The pattern which includes the addition of refrigerant mass will reach the optimum cabin temperature (achieve thermal comfort), and then decrease (the temperature will increase). The lowest temperature achieved in the cabin (24.6oC) was at a refrigerant volume of 700 ml.
Exosome-Laden Hydrogels: A Novel Cell-free Strategy for In-situ Bone Tissue Regeneration
Authors: Sun Jinru , Yin Zhifeng , Wang Xiuhui , Su Jiacan
Published: April 2022

In-situ bone tissue regeneration, which harnesses cell external microenvironment and their regenerative potential to induce cell functions and bone reconstruction through some special properties of biomaterials, has been deeply developed. In which, hydrogel was widely applied due to its 3D network structure with high water absorption and mimicking native extracellular matrix (ECM). Additionally, exosomes can participate in a variety of physiological processes such as cell differentiation, angiogenesis and tissue repair. Therefore, a novel cell-free tissue engineering (TE) using exosome-laden hydrogels has been explored and developed for bone regeneration in recent years. However, related reviews in this field are limited. Therefore, we elaborated on the shortcomings of traditional bone tissue engineering, the challenges of exosome delivery and emphasized the advantages of exosome-laden hydrogels for in-situ bone tissue regeneration. The encapsulation strategies of hydrogel and exosomes are listed, and the research progress and prospects of bioactive hydrogel composite system for continuous delivery of exosomes for in-situ bone repair are also discussed in this review.
Comprehensive Analysis of the Prognostic Signature of Mutation-Derived Genome Instability-Related lncRNAs for Patients With Endometrial Cancer
Authors: Liu Jinhui , Cui Guoliang , Ye Jun , Wang Yutong , Wang Can , Bai Jianling
Published: April 2022

Background: Emerging evidence shows that genome instability-related long non-coding RNAs (lncRNAs) contribute to tumor–cell proliferation, differentiation, and metastasis. However, the biological functions and molecular mechanisms of genome instability-related lncRNAs in endometrial cancer (EC) are underexplored.

Methods: EC RNA sequencing and corresponding clinical data obtained from The Cancer Genome Atlas (TCGA) database were used to screen prognostic lncRNAs associated with genomic instability via univariate and multivariate Cox regression analysis. The genomic instability-related lncRNA signature (GILncSig) was developed to assess the prognostic risk of high- and low-risk groups. The prediction performance was analyzed using receiver operating characteristic (ROC) curves. The immune status and mutational loading of different risk groups were compared. The Genomics of Drug Sensitivity in Cancer (GDSC) and the CellMiner database were used to elucidate the relationship between the correlation of prognostic lncRNAs and drug sensitivity. Finally, we used quantitative real-time PCR (qRT-PCR) to detect the expression levels of genomic instability-related lncRNAs in clinical samples.

Results: GILncSig was built using five lncRNAs (AC007389.3, PIK3CD-AS2, LINC01224, AC129507.4, and GLIS3-AS1) associated with genomic instability, and their expression levels were verified using qRT-PCR. Further analysis revealed that risk score was negatively correlated with prognosis, and the ROC curve demonstrated the higher accuracy of GILncSig. Patients with a lower risk score had higher immune cell infiltration, a higher immune score, lower tumor purity, higher immunophenoscores (IPSs), lower mismatch repair protein expression, higher microsatellite instability (MSI), and a higher tumor mutation burden (TMB). Furthermore, the level of expression of prognostic lncRNAs was significantly related to the sensitivity of cancer cells to anti-tumor drugs.

Conclusion: A novel signature composed of five prognostic lncRNAs associated with genome instability can be used to predict prognosis, influence immune status, and chemotherapeutic drug sensitivity in EC.
A scRNA-seq Approach to Identifying Changes in Spermatogonial Stem Cell Gene Expression Following in vitro Culture
Authors: De Oliveira Camila Salum , Nixon Brett , Lord Tessa
Published: April 2022

Spermatogonial stem cell (SSC) function is essential for male fertility, and these cells hold potential therapeutic value spanning from human infertility treatments to wildlife conservation. As in vitro culture is likely to be an integral component of many therapeutic pipelines, we have elected to explore changes in gene expression occurring in undifferentiated spermatogonia in culture that may be intertwined with the temporal reduction in regenerative capacity that they experience. Single cell RNA-sequencing analysis was conducted, comparing undifferentiated spermatogonia retrieved from the adult mouse testis with those that had been subjected to 10 weeks of in vitro culture. Although the majority of SSC signature genes were conserved between the two populations, a suite of differentially expressed genes were also identified. Gene ontology analysis revealed upregulated expression of genes involved in oxidative phosphorylation in cultured spermatogonia, along with downregulation of integral processes such as DNA repair and ubiquitin-mediated proteolysis. Indeed, our follow-up analyses have provided the first depiction of a significant accumulation of ubiquitinated proteins in cultured spermatogonia, when compared to those residing in the testis. The data produced in this manuscript will provide a valuable platform for future studies looking to improve SSC culture approaches and assess their safety for utilisation in therapeutic pipelines.
Sonic hedgehog is Essential for Proximal-Distal Outgrowth of the Limb Bud in Salamanders
Authors: Purushothaman Sruthi , Lopez Aviña Brianda B. , Seifert Ashley W.
Published: April 2022

The developing forelimb has been a foundational model to understand how specified progenitor cells integrate genetic information to produce the tetrapod limb bauplan. Although the reigning hypothesis is that all tetrapods develop limbs in a similar manner, recent work suggests that urodeles have evolved a derived mode of limb dvelopment. Here, we demonstrate through pharmacological and genetic inactivation of Sonic hedgehog (Shh) signaling in axolotls that Shh directs expansion and survival of limb progenitor cells in addition to patterning the limb across the proximodistal and antero-posterior axis. In contrast to inactivation of Shh in mouse or chick embryos where a humerus, radius, and single digit develop, Shh crispant axolotls completely lack forelimbs. In rescuing limb development by implanting SHH-N protein beads into the nascent limb field of Shh crispants, we show that the limb field is specified in the absence of Shh and that hedgehog pathway activation is required to initiate proximodistal outgrowth. When our results are examined alongside other derived aspects of salamander limb development and placed in a phylogenetic context, a new hypothesis emerges whereby the ability for cells at an amputation plane to activate morphogenesis and regenerate a limb may have evolved uniquely in urodeles.
Histone Modification Landscapes as a Roadmap for Malaria Parasite Development
Authors: Connacher J. , von Grüning H. , Birkholtz L.
Published: April 2022

Plasmodium falciparum remains the deadliest parasite species in the world, responsible for 229 million cases of human malaria in 2019. The ability of the P. falciparum parasite to progress through multiple life cycle stages and thrive in diverse host and vector species hinges on sophisticated mechanisms of epigenetic regulation of gene expression. Emerging evidence indicates such epigenetic control exists in concentric layers, revolving around core histone post-translational modification (PTM) landscapes. Here, we provide a necessary update of recent epigenome research in malaria parasites, focusing specifically on the ability of dynamic histone PTM landscapes to orchestrate the divergent development and differentiation pathways in P. falciparum parasites. In addition to individual histone PTMs, we discuss recent findings that imply functional importance for combinatorial PTMs in P. falciparum parasites, representing an operational histone code. Finally, this review highlights the remaining gaps and provides strategies to address these to obtain a more thorough understanding of the histone modification landscapes that are at the center of epigenetic regulation in human malaria parasites.
Cas9/AAV9-Mediated Somatic Mutagenesis Uncovered the Cell-Autonomous Role of Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 in Murine Cardiomyocyte Maturation
Authors: Lin Junsen , Chen Zhan , Yang Luzi , Liu Lei , Yue Peng , Sun Yueshen , Zhao Mingming , Guo Xiaoling , Hu Xiaomin , Zhang Yan , Zhang Hong , Li Yifei , Guo Yuxuan , Dong Erdan
Published: April 2022

Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) is a key player in cardiomyocyte calcium handling and also a classic target in the gene therapy for heart failure. SERCA2 expression dramatically increases during cardiomyocyte maturation in the postnatal phase of heart development, which is essential for the heart to acquire its full function in adults. However, whether and how SERCA2 regulates cardiomyocyte maturation remains unclear. Here, we performed Cas9/AAV9-mediated somatic mutagenesis (CASAAV) in mice and achieved cardiomyocyte-specific knockout of Atp2a2, the gene coding SERCA2. Through a cardiac genetic mosaic analysis, we demonstrated the cell-autonomous role of SERCA2 in building key ultrastructures of mature ventricular cardiomyocytes, including transverse-tubules and sarcomeres. SERCA2 also exerts a profound impact on oxidative respiration gene expression and sarcomere isoform switching from Myh7/Tnni1 to Myh6/Tnni3, which are transcriptional hallmarks of cardiomyocyte maturation. Together, this study uncovered a pivotal role of SERCA2 in heart development and provided new insights about SERCA2-based cardiac gene therapy.
Chromatin-Remodeling Factor BRG1 Is a Negative Modulator of L. donovani in IFNγ Stimulated and Infected THP-1 Cells
Authors: Brar Harsimran Kaur , Roy Gargi , Kanojia Akanksha , Madan Evanka , Madhubala Rentala , Muthuswami Rohini
Published: April 2022

Intracellular pathogens manipulate the host cell for their own survival by contributing to modifications of host epigenome, and thus, altering expression of genes involved in the pathogenesis. Both ATP-dependent chromatin remodeling complex and histone modifications has been shown to be involved in the activation of IFNγ responsive genes. Leishmania donovani is an intracellular pathogen that causes visceral leishmaniasis. The strategies employed by Leishmania donovani to modulate the host epigenome in order to overcome the host defense for their persistence has been worked out in this study. We show that L. donovani negatively affects BRG1, a catalytic subunit of mammalian SWI/SNF chromatin remodeling complex, to alter IFNγ induced host responses. We observed that L. donovani infection downregulates BRG1 expression both at transcript and protein levels in cells stimulated with IFNγ. We also observed a significant decrease in IFNγ responsive gene, Class II transactivator (CIITA), as well as its downstream genes, MHC-II (HLA-DR and HLA-DM). Also, the occupancy of BRG1 at CIITA promoters I and IV was disrupted. A reversal in CIITA expression and decreased parasite load was observed with BRG1 overexpression, thus, suggesting BRG1 is a potential negative regulator for the survival of intracellular parasites in an early phase of infection. We also observed a decrease in H3 acetylation at the promoters of CIITA, post parasite infection. Silencing of HDAC1, resulted in increased CIITA expression, and further decreased parasite load. Taken together, we suggest that intracellular parasites in an early phase of infection negatively regulates BRG1 by using host HDAC1 for its survival inside the host.
Sporadic Low Salinity Signals in the Oceanic Mixed Layer Observed by the Kuroshio Extension Observatory Buoy
Authors: Kameyama Kohei , Kanno Yuki , Ohishi Shun , Tomita Hiroyuki , Fukutomi Yoshiki , Aiki Hidenori
Published: April 2022

The hourly measurements of air-sea interaction parameters made at the Kuroshio Extension Observatory (KEO) buoy since 2004 have produced an extensive dataset that can be used to understand the dynamics of the oceanic mixed-layer under extreme weather conditions. Our analysis of the KEO-buoy measurements reveals the presence of sporadic low-salinity signals (SLSSs) with duration of 1–2 days in the mixed-layer when, for example, tropical cyclones (TCs) approach. Here SLSS events are identified within the buoy data by using a flag which is set to unity when the value of normalized salinity falls below −1 (minus one). Application of this definition to the hourly time series of salinity measured at 10 m depth by the KEO buoy has allowed us to identify 244 SLSS events over the 11-year analysis period. Both winter (January-March) and spring (April-June) seasons show a peak in the composite time series of wind velocity subdiurnal variation (WVDV) near the start time of SLSS events. SLSS events can be terminated by the entrainment of saltier subsurface water parcels to the mixed-layer in response to storms. The discovery of the WVDV peaks following SLSS commencement is the reason the present study has adopted a time scale of 1-day wind velocity analysis. This temporal resolution has enabled us to identify a TC-related delay in the development of the WVDV peaks, which may represent a fundamental characteristic of the influence of TCs on these events.
Association of Sleep Patterns and Lifestyles With Incident Hypertension: Evidence From a Large Population-Based Cohort Study
Authors: Lv Yanling , Jiang Guanhua , Tan Xiao , Bao Wei , Chen Liangkai , Liu Liegang
Published: April 2022

Background

Adherence to a healthy lifestyle (no smoking, consuming a healthy diet, engaging in physical activity, and maintaining a healthy weight) is recommended in current guidelines for hypertension prevention. However, evidence regarding the association between sleep behaviors, independently and jointly with traditional lifestyle factors, and the risk of hypertension is limited.

Methods

This prospective study included 165,493 participants who are free of hypertension at baseline from the UK Biobank. Sleep behaviors, including chronotype, sleep duration, insomnia, snoring, and daytime sleepiness were used to construct a healthy sleep score. We also derived a healthy lifestyle score based on smoking status, diet quality, physical activity, and body mass index (BMI). Cox proportional hazards regression models and competing risk analyses were used to estimate the associations of the healthy sleep score and healthy lifestyle score with the risk of hypertension. The population attributable risk percent (PAR%) was estimated for increased cases of hypertension due to poor adherence to a healthy sleep pattern or a healthy lifestyle.

Results

A total of 10,941 incident hypertension cases were documented during a median of 11.8 years of follow-up. The multivariable-adjusted hazard ratio (HR) for hypertension was 0.58 [95% confidence interval (CI): 0.52, 0.65] for participants with a sleep score of 5 compared with 0–1, and 0.48 (95% CI: 0.43, 0.54) for participants with a lifestyle score of 4 compared with those who scored 0. For joint association, those with a poor sleep pattern and a poor lifestyle had the highest risk of hypertension [HR: 2.41 (95% CI: 2.12, 2.74)]. PAR% was 14.7% (95% CI: 12.3%, 17.1%), 20.1% (95% CI: 17.6%, 22.6%), and 31.7% (95% CI: 27.6%, 35.6%) for poor adherence to a healthy sleep pattern, a healthy lifestyle, and the combination of a healthy sleep pattern and a healthy lifestyle.

Conclusion

Both a healthy sleep pattern and a healthy lifestyle were associated with a lower risk of hypertension, and the benefits of adhering to a healthy sleep pattern complement the well-established lifestyle for the optimal primary prevention of hypertension. These findings support the current perspective that a healthy sleep pattern is an important part of a healthful and productive lifestyle for hypertension prevention.
Oral Senescence: From Molecular Biology to Clinical Research
Authors: Parkinson Eric Kenneth , Prime Stephen Stewart
Published: April 2022

Cellular senescence is an irreversible cell cycle arrest occurring following multiple rounds of cell division (replicative senescence) or in response to cellular stresses such as ionizing radiation, signaling imbalances and oxidative damage (stress-induced premature senescence). Even very small numbers of senescent cells can be deleterious and there is evidence that senescent cells are instrumental in a number of oral pathologies including cancer, oral sub mucous fibrosis and the side effects of cancer therapy. In addition, senescent cells are present and possibly important in periodontal disease and other chronic inflammatory conditions of the oral cavity. However, senescence is a double-edged sword because although it operates as a suppressor of malignancy in pre-malignant epithelia, senescent cells in the neoplastic environment promote tumor growth and progression. Many of the effects of senescent cells are dependent on the secretion of an array of diverse therapeutically targetable proteins known as the senescence-associated secretory phenotype. However, as senescence may have beneficial roles in wound repair, preventing fibrosis and stem cell activation the clinical exploitation of senescent cells is not straightforward. Here, we discuss biological mechanisms of senescence and we review the current approaches to target senescent cells therapeutically, including senostatics and senolytics which are entering clinical trials.
Shallow Depth, Substantial Change: Fluid-Metasomatism Causes Major Compositional Modifications of Subducted Volcanics (Mariana Forearc)
Authors: Albers Elmar , Shervais John W. , Hansen Christian T. , Ichiyama Yuji , Fryer Patricia
Published: April 2022

Mass transfer at shallow subduction levels and its ramifications for deeper processes remain incompletely constrained. New insights are provided by ocean island basalt (OIB) clasts from the Mariana forearc that experienced subduction to up to ∼25–30 km depth and up to blueschist-facies metamorphism; thereafter, the clasts were recycled to the forearc seafloor via serpentinite mud volcanism. We demonstrate that the rocks were, in addition, strongly metasomatized: they exhibit K2O contents (median = 4.6 wt%) and loss on ignition (median = 5.3 wt%, as a proxy for H2O) much higher than OIB situated on the Pacific Plate, implying that these were added during subduction. This interpretation is consistent with abundant phengite in the samples. Mass balance calculations further reveal variable gains in SiO2 for all samples, and increased MgO and Na2O at one but losses of MgO and Fe2O3* at the other study site. Elevated Cs and Rb concentrations suggest an uptake whereas low Ba and Sr contents indicate the removal of trace elements throughout all clasts. The metasomatism was likely induced by the OIBs’ interaction with K-rich fluids in the subduction channel. Our thermodynamic models imply that such fluids are released from subducted sediments and altered igneous crust at 5 kbar and even below 200°C. Equilibrium assemblage diagrams show that the stability field of phengite significantly increases with the metasomatism and that, relative to not-metasomatized OIB, up to four times as much phengite may form in the metasomatized rocks. Phengite in turn is considered as an important carrier for K2O, H2O, and fluid-mobile elements to sub-arc depths. These findings demonstrate that mass transfer from the subducting lithosphere starts at low P/T conditions. The liberation of solute-rich fluids can evoke far-reaching compositional and mineralogical changes in rocks that interact with these fluids. Processes at shallow depths (<30 km) thereby contribute to controlling which components as well as in which state (i.e., bound in which minerals) these components ultimately reach greater depths where they may or may not contribute to arc magmatism. For a holistic understanding of deep geochemical cycling, metasomatism and rock transformation need to be acknowledged from shallow depths on.
Generation and Characterization of iPS Cells Derived from APECED Patients for Gene Correction
Authors: Karvonen Eira , Krohn Kai J. E. , Ranki Annamari , Hau Annika
Published: April 2022

APECED (Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy) is a severe and incurable multiorgan autoimmune disease caused by mutations in the AIRE (autoimmune regulator) gene. Without functional AIRE, the development of central and peripheral immune tolerance is severely impaired allowing the accumulation of autoreactive immune cells in the periphery. This leads to multiple endocrine and non-endocrine autoimmune disorders and mucocutaneous candidiasis in APECED patients. Recent studies have suggested that AIRE also has novel functions in stem cells and contributes to the regulatory network of pluripotency. In preparation of therapeutic gene correction, we generated and assessed patient blood cell-derived iPSCs, potentially suitable for cell therapy in APECED. Here, we describe APECED-patient derived iPSCs’s properties, expression of AIRE as well as classical stem cell markers by qPCR and immunocytochemistry. We further generated self-aggregated EBs of the iPSCs. We show that APECED patient-derived iPSCs and EBs do not have any major proliferative or apoptotic defects and that they express all the classical pluripotency markers similarly to healthy person iPSCs. The results suggest that the common AIRE R257X truncation mutation does not affect stem cell properties and that APECED iPSCs can be propagated in vitro and used for subsequent gene-correction. This first study on APECED patient-derived iPSCs validates their pluripotency and confirms their ability for differentiation and potential therapeutic use.
Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation
Authors: Jiang Ying , Zhu Hong , Chen Zi , Yu Yi-Chen , Guo Xiao-Han , Chen Yuan , Yang Meng-Meng , Chen Bang-Wu , Sagnelli Matthew , Xu Dong , Zhao Bai-Hui , Luo Qiong
Published: April 2022

Objective

The offspring of women with gestational diabetes mellitus (GDM) have a high predisposition to developing type 2 diabetes during childhood and adulthood. The aim of the study was to evaluate how GDM exposure in the second half of pregnancy contributes to hepatic glucose intolerance through a mouse model.

Methods

By creating a GDM mouse model, we tested glucose and insulin tolerance of offspring by intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). In addition, we checked the expression of genes IGF2/H19, FoxO1, and DNMTs in the mouse liver by RT-qPCR. Pyrosequencing was used to detect the methylation status on IGF2/H19 differentially methylated regions (DMRs). In vitro insulin stimulation experiments were performed to evaluate the effect of different insulin concentrations on HepG2 cells. Moreover, we detect the interaction between FoxO1 and DNMT3A by chromatin immunoprecipitation–quantitative PCR (Chip-qPCR) and knock-down experiments on HepG2 cells.

Results

We found that the first generation of GDM offspring (GDM-F1) exhibited impaired glucose tolerance (IGT) and insulin resistance, with males being disproportionately affected. In addition, the expression of imprinted genes IGF2 and H19 was downregulated in the livers of male mice via hypermethylation of IGF2-DMR0 and IGF2-DMR1. Furthermore, increased expression of transcriptional factor FoxO1 was confirmed to regulate DNMT3A expression, which contributed to abnormal methylation of IGF2/H19 DMRs. Notably, different insulin treatments on HepG2 demonstrated those genetic alterations, suggesting that they might be induced by intrauterine hyperinsulinemia.

Conclusion

Our results demonstrated that the intrauterine hyperinsulinemia environment has increased hepatic FoxO1 levels and subsequently increased expression of DNMT3A and epigenetic alterations on IGF2/H19 DMRs. These findings provide potential molecular mechanisms responsible for glucose intolerance and insulin resistance in the first male generation of GDM mice.
Unconventional Oil Prospects and Challenges in the Covid-19 Era
Authors: Eveloy Valerie , Elsheikh Hassan
Published: April 2022

Fossil fuels will continue to play an important role for the forthcoming decades, including in key hard-to-abate transport and industrial sectors. Unconventional oil (UO) has emerged as a sizeable contributor to meeting the global energy demand in the energy transition period. However, unfavorable circumstances compounded by the Covid-19 pandemic have intensified uncertainties and speculation regarding the future prospects of these resources. This mini-review explores prospects and challenges faced by UO development in the Covid-19 era, focusing on technical, economic, energy security, and environmental sustainability aspects. While UOs have been significantly affected by the pandemic in the short term, limited medium to long-term UO projections exist, with contrasted findings. The review reveals the multiplicity and complexity of interactions between the Covid-19 pandemic and the discussed UO aspects, the diversity of views, and conflicting short- and long-term goals of the energy industry.
Decosus: An R Framework for Universal Integration of Cell Proportion Estimation Methods
Authors: Anene Chinedu A. , Taggart Emma , Harwood Catherine A. , Pennington Daniel J. , Wang Jun
Published: April 2022

The assessment of the cellular heterogeneity and abundance in bulk tissue samples is essential for characterising cellular and organismal states. Computational approaches to estimate cellular abundance from bulk RNA-Seq datasets have variable performances, often requiring benchmarking matrices to select the best performing methods for individual studies. However, such benchmarking investigations are difficult to perform and assess in typical applications because of the absence of gold standard/ground-truth cellular measurements. Here we describe Decosus, an R package that integrates seven methods and signatures for deconvoluting cell types from gene expression profiles (GEP). Benchmark analysis on a range of datasets with ground-truth measurements revealed that our integrated estimates consistently exhibited stable performances across datasets than individual methods and signatures. We further applied Decosus to characterise the immune compartment of skin samples in different settings, confirming the well-established Th1 and Th2 polarisation in psoriasis and atopic dermatitis, respectively. Secondly, we revealed immune system-related UV-induced changes in sun-exposed skin. Furthermore, a significant motivation in the design of Decosus is flexibility and the ability for the user to include new gene signatures, algorithms, and integration methods at run time.
The Role of Copy Number Variants in Gene Co-Expression Patterns for Luminal B Breast Tumors
Authors: Hernández-Gómez Candelario , Hernández-Lemus Enrique , Espinal-Enríquez Jesús
Published: April 2022

Gene co-expression networks have become a usual approach to integrate the vast amounts of information coming from gene expression studies in cancer cohorts. The reprogramming of the gene regulatory control and the molecular pathways depending on such control are central to the characterization of the disease, aiming to unveil the consequences for cancer prognosis and therapeutics. There is, however, a multitude of factors which have been associated with anomalous control of gene expression in cancer. In the particular case of co-expression patterns, we have previously documented a phenomenon of loss of long distance co-expression in several cancer types, including breast cancer. Of the many potential factors that may contribute to this phenomenology, copy number variants (CNVs) have been often discussed. However, no systematic assessment of the role that CNVs may play in shaping gene co-expression patterns in breast cancer has been performed to date. For this reason we have decided to develop such analysis. In this study, we focus on using probabilistic modeling techniques to evaluate to what extent CNVs affect the phenomenon of long/short range co-expression in Luminal B breast tumors. We analyzed the co-expression patterns in chromosome 8, since it is known to be affected by amplifications/deletions during cancer development. We found that the CNVs pattern in chromosome 8 of Luminal B network does not alter the co-expression patterns significantly, which means that the co-expression program in this cancer phenotype is not determined by CNV structure. Additionally, we found that region 8q24.3 is highly dense in interactions, as well as region p21.3. The most connected genes in this network belong to those cytobands and are associated with several manifestations of cancer in different tissues. Interestingly, among the most connected genes, we found MAF1 and POLR3D, which may constitute an axis of regulation of gene transcription, in particular for non-coding RNA species. We believe that by advancing on our knowledge of the molecular mechanisms behind gene regulation in cancer, we will be better equipped, not only to understand tumor biology, but also to broaden the scope of diagnostic, prognostic and therapeutic interventions to ultimately benefit oncologic patients.
Multi-Omics Reveals Different Strategies in the Immune and Metabolic Systems of High-Yielding Strains of Laying Hens
Authors: Iqbal Muhammad Arsalan , Reyer Henry , Oster Michael , Hadlich Frieder , Trakooljul Nares , Perdomo-Sabogal Alvaro , Schmucker Sonja , Stefanski Volker , Roth Christoph , Camarinha Silva Amélia , Huber Korinna , Sommerfeld Vera , Rodehutscord Markus , Wimmers Klaus , Ponsuksili Siriluck
Published: April 2022

Lohmann Brown (LB) and Lohmann Selected Leghorn (LSL) are two commercially important laying hen strains due to their high egg production and excellent commercial suitability. The present study integrated multiple data sets along the genotype-phenotype map to better understand how the genetic background of the two strains influences their molecular pathways. In total, 71 individuals were analyzed (LB, n = 36; LSL, n = 35). Data sets include gut miRNA and mRNA transcriptome data, microbiota composition, immune cells, inositol phosphate metabolites, minerals, and hormones from different organs of the two hen strains. All complex data sets were pre-processed, normalized, and compatible with the mixOmics platform. The most discriminant features between two laying strains included 20 miRNAs, 20 mRNAs, 16 immune cells, 10 microbes, 11 phenotypic traits, and 16 metabolites. The expression of specific miRNAs and the abundance of immune cell types were related to the enrichment of immune pathways in the LSL strain. In contrast, more microbial taxa specific to the LB strain were identified, and the abundance of certain microbes strongly correlated with host gut transcripts enriched in immunological and metabolic pathways. Our findings indicate that both strains employ distinct inherent strategies to acquire and maintain their immune and metabolic systems under high-performance conditions. In addition, the study provides a new perspective on a view of the functional biodiversity that emerges during strain selection and contributes to the understanding of the role of host–gut interaction, including immune phenotype, microbiota, gut transcriptome, and metabolome.
An Interpretable Double-Scale Attention Model for Enzyme Protein Class Prediction Based on Transformer Encoders and Multi-Scale Convolutions
Authors: Lin Ken , Quan Xiongwen , Jin Chen , Shi Zhuangwei , Yang Jinglong
Published: April 2022

Background Classification and annotation of enzyme proteins are fundamental for enzyme research on biological metabolism. Enzyme Commission (EC) numbers provide a standard for hierarchical enzyme class prediction, on which several computational methods have been proposed. However, most of these methods are dependent on prior distribution information and none explicitly quantifies amino-acid-level relations and possible contribution of sub-sequences.

Methods In this study, we propose a double-scale attention enzyme class prediction model named DAttProt with high reusability and interpretability. DAttProt encodes sequence by self-supervised Transformer encoders in pre-training and gathers local features by multi-scale convolutions in fine-tuning. Specially, a probabilistic double-scale attention weight matrix is designed to aggregate multi-scale features and positional prediction scores. Finally, a full connection linear classifier conducts a final inference through the aggregated features and prediction scores.

Results On DEEPre and ECPred datasets, DAttProt performs as competitive with the compared methods on level 0 and outperforms them on deeper task levels, reaching 0.788 accuracy on level 2 of DEEPre and 0.967 macro-F1 on level 1 of ECPred. Moreover, through case study, we demonstrate that the double-scale attention matrix learns to discover and focus on the positions and scales of bio-functional sub-sequences in the protein.

Conclusion Our DAttProt provides an effective and interpretable method for enzyme class prediction. It can predict enzyme protein classes accurately and furthermore discover enzymatic functional sub-sequences such as protein motifs from both positional and spatial scales.
Fungal CNS Infections in Africa: The Neuroimmunology of Cryptococcal Meningitis
Authors: Mohamed Sally H. , Nyazika Tinashe K. , Ssebambulidde Kenneth , Lionakis Michail S. , Meya David B. , Drummond Rebecca A.
Published: April 2022

Cryptococcal meningitis (CM) is the leading cause of central nervous system (CNS) fungal infections in humans, with the majority of cases reported from the African continent. This is partly due to the high burden of HIV infection in the region and reduced access to standard-of-care including optimal sterilising antifungal drug treatments. As such, CM is responsible for 10-15% of all HIV-related mortality, with a large proportion being preventable. Immunity to the causative agent of CM, Cryptococcus neoformans, is only partially understood. IFNγ producing CD4+ T-cells are required for the activation of myeloid cells, especially macrophages, to enable fungal killing and clearance. However, macrophages may also act as a reservoir of the fungal yeast cells, shielding them from host immune detection thus promoting latent infection or persistent chronic inflammation. In this chapter, we review the epidemiology and pathogenesis of CNS fungal infections in Africa, with a major focus on CM, and the antifungal immune pathways operating to protect against C. neoformans infection. We also highlight the areas of research and policy that require prioritisation to help reduce the burden of CNS fungal diseases in Africa.
Designing a Novel Functional Peptide With Dual Antimicrobial and Anti-inflammatory Activities via in Silico Methods
Authors: Shin Min Kyoung , Lee Byungjo , Kim Seung Tae , Yoo Jung Sun , Sung Jung-Suk
Published: April 2022

As spider venom is composed of various bioactive substances, it can be utilized as a platform for discovering future therapeutics. Host defense peptides are great candidates for developing novel antimicrobial agents due to their multifunctional properties. In this study, novel functional peptides were rationally designed to have dual antibacterial and anti-inflammatory activities with high cytocompatibility. Based on a template sequence from the transcriptome of spider Agelena koreana, a series of via in silico analysis were conducted, incorporating web-based machine learning tools along with the alteration of amino acid residues. Two peptides, Ak-N’ and Ak-N’m, were designed and were subjected to functional validation. The peptides inhibited gram-negative and gram-positive bacteria by disrupting the outer and bacterial cytoplasmic membrane. Moreover, the peptides down-regulated the expression of pro-inflammatory mediators, tumor necrosis factor-α, interleukin (IL)-1β, and IL6. Along with low cytotoxicity, Ak-N’m was shown to interact with macrophage surface receptors, inhibiting both Myeloid differentiation primary response 88-dependent and TIR-domain-containing adapter-inducing interferon-β-dependent pathways of Toll-like receptor 4 signaling on lipopolysaccharide-stimulated THP-1-derived macrophages. Here, we rationally designed functional peptides based on the suggested in silico strategy, demonstrating new insights for utilizing biological resources as well as developing therapeutic agents with enhanced properties.
The Role of DNA Repair in Immunological Diversity: From Molecular Mechanisms to Clinical Ramifications
Authors: Gullickson Peter , Xu Yunwen W. , Niedernhofer Laura J. , Thompson Elizabeth L. , Yousefzadeh Matthew J.
Published: April 2022

An effective humoral immune response necessitates the generation of diverse and high-affinity antibodies to neutralize pathogens and their products. To generate this assorted immune repertoire, DNA damage is introduced at specific regions of the genome. Purposeful genotoxic insults are needed for the successful completion of multiple immunological diversity processes: V(D)J recombination, class-switch recombination, and somatic hypermutation. These three processes, in concert, yield a broad but highly specific immune response. This review highlights the importance of DNA repair mechanisms involved in each of these processes and the catastrophic diseases that arise from DNA repair deficiencies impacting immune system function. These DNA repair disorders underline not only the importance of maintaining genomic integrity for preventing disease but also for robust adaptive immunity.