Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was considered “undruggable” for decades, specific KRAS G12C covalent inhibitors have recently emerged, although their promising results are limited to a subset of patients. Several other drugs targeting KRAS activation and downstream signaling pathways are currently under investigation in early-phase clinical trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes different responses to therapies. This review describes the molecular characterization of KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.
Serotype Distribution, Antimicrobial Susceptibility, Multilocus Sequencing Type and Virulence of Invasive Streptococcus pneumoniae in China: A Six-Year Multicenter Study

Background: Streptococcus pneumoniae is an important human pathogen that can cause severe invasive pneumococcal diseases (IPDs). The aim of this multicenter study was to investigate the serotype and sequence type (ST) distribution, antimicrobial susceptibility, and virulence of S. pneumoniae strains causing IPD in China. Methods: A total of 300 invasive S. pneumoniae isolates were included in this study. The serotype, ST, and antimicrobial susceptibility of the strains, were determined by the Quellung reaction, multi-locus sequence typing (MLST) and broth microdilution method, respectively. The virulence level of the strains in the most prevalent serotypes was evaluated by a mouse sepsis model, and the expression level of well-known virulence genes was measured by RT-PCR. Results: The most common serotypes in this study were 23F, 19A, 19F, 3, and 14. The serotype coverages of PCV7, PCV10, PCV13, and PPV23 vaccines on the strain collection were 42.3, 45.3, 73.3 and 79.3%, respectively. The most common STs were ST320, ST81, ST271, ST876, and ST3173. All strains were susceptible to ertapenem, levofloxacin, moxifloxacin, linezolid, and vancomycin, but a very high proportion (>95%) was resistant to macrolides and clindamycin. Based on the oral, meningitis and non-meningitis breakpoints, penicillin non-susceptible Streptococcus pneumoniae (PNSP) accounted for 67.7, 67.7 and 4.3% of the isolates, respectively. Serotype 3 strains were characterized by high virulence levels and low antimicrobial-resistance rates, while strains of serotypes 23F, 19F, 19A, and 14, exhibited low virulence and high resistance rates to antibiotics. Capsular polysaccharide and non-capsular virulence factors were collectively responsible for the virulence diversity of S. pneumoniae strains. Conclusion: Our study provides a comprehensive insight into the epidemiology and virulence diversity of S. pneumoniae strains causing IPD in China.
Consumer Motivations for Adopting Omnichannel Retailing: A Safety-Driven Perspective in the Context of COVID-19

This study aims to understand the influence of COVID-19 on consumers' fears and self-protection motivations. Furthermore, the study seeks to understand the effects of these fears and motivations on consumers' intentions to use omnichannel retailing. A modified theoretical model is proposed by integrating protection motivation theory (PMT) and extending the extended parallel process model (E-EPPM). A total of 398 valid questionnaires are collected and used for further structural equation modeling analysis. The results suggest that the perceived severity, perceived vulnerability, and health anxiety positively impact perceived fears surrounding COVID-19. Furthermore, it is found that perceived fear, self-efficacy, and response efficacy will affect the protection motivation of consumers and ultimately contribute to their behavioral intention to use omnichannel retailing. The findings theoretically enrich the research on COVID-19, PMT, and E-EPPM and empirically provide managerial implications for omnichannel retail service providers.
The Interplay Between Neuroinfections, the Immune System and Neurological Disorders: A Focus on Africa

Neurological disorders related to neuroinfections are highly prevalent in Sub-Saharan Africa (SSA), constituting a major cause of disability and economic burden for patients and society. These include epilepsy, dementia, motor neuron diseases, headache disorders, sleep disorders, and peripheral neuropathy. The highest prevalence of human immunodeficiency virus (HIV) is in SSA. Consequently, there is a high prevalence of neurological disorders associated with HIV infection such as HIV-associated neurocognitive disorders, motor disorders, chronic headaches, and peripheral neuropathy in the region. The pathogenesis of these neurological disorders involves the direct role of the virus, some antiretroviral treatments, and the dysregulated immune system. Furthermore, the high prevalence of epilepsy in SSA (mainly due to perinatal causes) is exacerbated by infections such as toxoplasmosis, neurocysticercosis, onchocerciasis, malaria, bacterial meningitis, tuberculosis, and the immune reactions they elicit. Sleep disorders are another common problem in the region and have been associated with infectious diseases such as human African trypanosomiasis and HIV and involve the activation of the immune system. While most headache disorders are due to benign primary headaches, some secondary headaches are caused by infections (meningitis, encephalitis, brain abscess). HIV and neurosyphilis, both common in SSA, can trigger long-standing immune activation in the central nervous system (CNS) potentially resulting in dementia. Despite the progress achieved in preventing diseases from the poliovirus and retroviruses, these microbes may cause motor neuron diseases in SSA. The immune mechanisms involved in these neurological disorders include increased cytokine levels, immune cells infiltration into the CNS, and autoantibodies. This review focuses on the major neurological disorders relevant to Africa and neuroinfections highly prevalent in SSA, describes the interplay between neuroinfections, immune system, neuroinflammation, and neurological disorders, and how understanding this can be exploited for the development of novel diagnostics and therapeutics for improved patient care.
Endothelial Cell Distribution After Flow Exposure With Two Stent Struts Placed in Different Angles

Stent implantation has been a primary treatment for stenosis and other intravascular diseases. However, the struts expansion procedure might cause endothelium lesion and the structure of the struts could disturb the blood flow environment near the wall of the blood vessel. These changes could damage the vascular innermost endothelial cell (EC) layer and pose risks of restenosis and post-deployment thrombosis. This research aims to investigate the effect of flow alterations on EC distribution in the presence of gap between two struts within the parallel flow chamber. To study how the gap presence impacts EC migration and the endothelialization effect on the surface of the struts, two struts were placed with specific orientations and positions on the EC layer in the flow chamber. After a 24-h exposure under wall shear stress (WSS), we observed the EC distribution conditons especially in the gap area. We also conducted computational fluid dynamics (CFD) simulations to calculate the WSS distribution. High EC-concentration areas on the bottom plate corresponded to the high WSS by the presence of gap between the two struts. To find the relation between the WSS and EC distributions on the fluorescence images, WSS condition by CFD simulation could be helpful for the EC distribution. The endothelialization rate, represented by EC density, on the downstream sides of both struts was higher than that on the upstream sides. These observations were made in the flow recirculation at the gap area between two struts. On two side surfaces between the gaps, meaning the downstream at the first and the upstream at the second struts, EC density differences on the downstream surfaces of the first strut were higher than on the upstream surfaces of the second strut. Finally, EC density varied along the struts when the struts were placed at tilted angles. These results indicate that, by the presence of gap between the struts, ECs distribution could be predicted in both perpendicular and tiled positions. And tiled placement affect ECs distribution on the strut side surfaces.
Transcriptomic and Lipidomic Profiles in Nasal Polyps of Glucocorticoid Responders and Non-Responders: Before and After Treatment

Background: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and mechanisms underlying different responses to systemic glucocorticoids (GC) remain unclear. The major aim of this study was to explore the transcriptomic and oxidative lipidomic signatures and the effects of GC in patients with different clinical responses. Methods: Nasal polyp biopsies were obtained before and after 14-day oral GC treatment from 16 patients with CRSwNP, and normal nasal mucosa specimens were collected from 12 control subjects. RNA sequencing and oxidative lipidomics were performed, and differential gene expression analysis was conducted in the Responder and Non-responder groups at baseline and after treatment. Results: In the Responder group, GC significantly improved clinical symptoms and reduced tissue eosinophil infiltration. Meanwhile, GC led to a pronounced transcriptomic reversion with robust suppression of inflammatory responses and abnormal metabolism of extracellular matrix, as well as restoration of cilia function. However, non-responders were mainly characterized by epithelial hyperplasia and keratinization, with much less transcriptomic improvement after GC treatment. Higher expression of type 2 inflammatory molecules (CCL13, IGHE, CCL18, CCL23, CCR3, and CLC) with lower levels of LACRT, PPDPFL, DES, C6, MUC5B, and SCGB3A1 were related to a stronger clinical response to GC. Besides decreased prostaglandins and increased leukotrienes, increased dysregulation in other oxylipid mediators derived from polyunsaturated fatty acids was determined in nasal polyps, which was ameliorated by GC treatment. Conclusion: Systemic GC exert anti-inflammatory effects, improve tissue remodeling, restore cilia function, and ameliorate dysregulation of oxylipid mediator pathway in CRSwNP. GC-responders exhibited different transcriptomic signatures from non-responders.
Allelic Variants Within the ABO Blood Group Phenotype Confer Protection Against Critical COVID-19 Hospital Presentation

Introduction: Coronavirus disease 2019 (COVID-19) disease severity differs widely due to numerous factors including ABO gene-derived susceptibility or resistance. The objective of this study was to investigate the association of the ABO blood group and genetic variations of the ABO gene with COVID-19 severity in a heterogeneous hospital population sample from the United Arab Emirates, with the use of an epidemiological and candidate gene approach from a genome-wide association study (GWAS). Methods: In this cross-sectional study, a total of 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were recruited from multiple hospitals and population-based (quarantine camps) recruitment sites from March 2020 to February 2021. The participants were divided into two groups based on the severity of COVID-19: noncritical (n = 453) and critical [intensive care unit (ICU) patients] (n = 193), as per the COVID-19 Reporting and Data System (CO-RADS) classification. The multivariate logistic regression analysis demonstrated the association of ABO blood type as well as circulating anti-A antibodies and anti-B antibodies as well as A and B antigens, in association with critical COVID-19 hospital presentation. A candidate gene analysis approach was conducted from a GWAS where we examined 240 single nucleotide polymorphisms (SNPs) (position in chr9: 136125788-136150617) in the ABO gene, in association with critical COVID-19 hospital presentation. Results: Patients with blood group O [odds ratio (OR): 0.51 (0.33, 0.79); p = 0.003] were less likely to develop critical COVID-19 symptoms. Eight alleles have been identified to be associated with a protective effect of blood group O in ABO 3'untranslated region (UTR): rs199969472 (p = 0.0052), rs34266669 (p = 0.0052), rs76700116 (p = 0.0052), rs7849280 (p = 0.0052), rs34039247 (p = 0.0104), rs10901251 (p = 0.0165), rs9411475 (p = 0.0377), and rs13291798 (p = 0.0377). Conclusion: Our findings suggest that there are novel allelic variants that link genetic variants of the ABO gene and ABO blood groups contributing to the reduced risk of critical COVID-19 disease. This study is the first study to combine genetic and serological evidence of the involvement of the ABO blood groups and the ABO gene allelic associations with COVID-19 severity within the Middle Eastern population.
Genetic Diversity in the Italian Holstein Dairy Cattle Based on Pedigree and SNP Data Prior and After Genomic Selection

Genetic diversity has become an urgent matter not only in small local breeds but also in more specialized ones. While the use of genomic data in livestock breeding programs increased genetic gain, there is increasing evidence that this benefit may be counterbalanced by the potential loss of genetic variability. Thus, in this study, we aimed to investigate the genetic diversity in the Italian Holstein dairy cattle using pedigree and genomic data from cows born between 2002 and 2020. We estimated variation in inbreeding, effective population size, and generation interval and compared those aspects prior to and after the introduction of genomic selection in the breed. The dataset contained 84,443 single-nucleotide polymorphisms (SNPs), and 74,485 cows were analyzed. Pedigree depth based on complete generation equivalent was equal to 10.67. A run of homozygosity (ROH) analysis was adopted to estimate SNP-based inbreeding (FROH). The average pedigree inbreeding was 0.07, while the average FROH was more than double, being equal to 0.17. The pattern of the effective population size based on pedigree and SNP data was similar although different in scale, with a constant decrease within the last five generations. The overall inbreeding rate (ΔF) per year was equal to +0.27% and +0.44% for Fped and FROH throughout the studied period, which corresponded to about +1.35% and +2.2% per generation, respectively. A significant increase in the ΔF was found since the introduction of genomic selection in the breed. This study in the Italian Holstein dairy cattle showed the importance of controlling the loss of genetic diversity to ensure the long-term sustainability of this breed, as well as to guarantee future market demands.
Mesenchymal Stem-Cell Derived Exosome Therapy as a Potential Future Approach for Treatment of Male Infertility Caused by Chlamydia Infection

Some microbial sexually transmitted infections (STIs) have adverse effects on the reproductive tract, sperm function, and male fertility. Given that STIs are often asymptomatic and cause major complications such as urogenital inflammation, fibrosis, and scarring, optimal treatments should be performed to prevent the noxious effect of STIs on male fertility. Among STIs, Chlamydia trachomatis is the most common asymptomatic preventable bacterial STI. C. trachomatis can affect both sperm and the male reproductive tract. Recently, mesenchymal stem cells (MSCs) derived exosomes have been considered as a new therapeutic medicine due to their immunomodulatory, anti-inflammatory, anti-oxidant, and regenerative effects without consequences through the stem cell transplantation based therapies. Inflammation of the genital tract and sperm dysfunction are the consequences of the microbial infections, especially Chlamydia trachomatis. Exosome therapy as a noninvasive approach has shown promising results on the ability to regenerate the damaged sperm and treating asthenozoospermia. Recent experimental methods may be helpful in the novel treatments of male infertility. Thus, it is demonstrated that exosomes play an important role in preventing the consequences of infection, and thereby preventing inflammation, reducing cell damage, inhibiting fibrogenesis, and reducing scar formation. This review aimed to overview the studies about the potential therapeutic roles of MSCs-derived exosomes on sperm abnormalities and male infertility caused by STIs.
The Rice Abscisic Acid-Responsive RING Finger E3 Ligase OsRF1 Targets OsPP2C09 for Degradation and Confers Drought and Salinity Tolerance in Rice

Drought and salinity are major important factors that restrain growth and productivity of rice. In plants, many really interesting new gene (RING) finger proteins have been reported to enhance drought and salt tolerance. However, their mode of action and interacting substrates are largely unknown. Here, we identified a new small RING-H2 type E3 ligase OsRF1, which is involved in the ABA and stress responses of rice. OsRF1 transcripts were highly induced by ABA, salt, or drought treatment. Upregulation of OsRF1 in transgenic rice conferred drought and salt tolerance and increased endogenous ABA levels. Consistent with this, faster transcriptional activation of key ABA biosynthetic genes, ZEP, NCED3, and ABA4, was observed in OsRF1-OE plants compared with wild type in response to drought stress. Yeast two-hybrid assay, BiFC, and co-immunoprecipitation analysis identified clade A PP2C proteins as direct interacting partners with OsRF1. In vitro ubiquitination assay indicated that OsRF1 exhibited E3 ligase activity, and that it targeted OsPP2C09 protein for ubiquitination and degradation. Cell-free degradation assay further showed that the OsPP2C09 protein is more rapidly degraded by ABA in the OsRF1-OE rice than in the wild type. The combined results suggested that OsRF1 is a positive player of stress responses by modulating protein stability of clade A PP2C proteins, negative regulators of ABA signaling.
IL-33 and Soluble ST2 Are Associated With Recurrent Spontaneous Abortion in Early Pregnancy

Normal pregnancy is related to the successful transition from type 1 cellular immunity to type 2 cellular immunity. Therefore, this study aimed to investigate whether there is abnormal expression of cytokines in the process of inducing Recurrent spontaneous abortion (RSA). Interleukin (IL)-33 is a new member of the IL-1 family, and ST2, as IL-33’s receptor, induced the production of type 2 cytokines. In this study, blood samples were collected from 19 non-pregnant women of normal childbearing age, 28 normal pregnant women, and 33 women with RSA. The serum concentrations of IL-33 and ST2 were detected by flow cytometry. Our results showed that the serum concentrations of IL-33 and ST2 in the RSA group were significantly higher than those in the healthy control group (IL-33: P < 0.05; ST2: P < 0.0001), and IL-33 and ST2 had a higher level in the process of RSA predictive value. In addition, this study initially found that the serum concentrations of IL-33 and ST2 were not significantly correlated with the number of weeks of pregnancy, and there was a lower correlation between IL-33 and ST2 during RSA. This result may be related to the small number of cases. This study is the first time to correlate the changes in serum concentrations of IL-33 and ST2 with RSA, which may be a novel biomarker for the prediction and treatment of RSA.
Prevalence of

There are recent reports on the role of Helicobacter pylori in the promotion of tumor growth in extra-gastric organs, of which its role in colorectal neoplasm is gaining interest. We carried out a prospective cross-sectional prevalence study to evaluate the association of Helicobacter pylori and colorectal malignancy. It is a single-center cross-sectional prevalence study. The study group (n = 47) included all consecutive patients of age ≥ 18 years with colorectal malignancy. The control group (n = 43) included ageand gender-matched participants. Both groups were investigated for serum CagA antibodies and stool antigen for Helicobacter pylori and results were analyzed with different tumor parameters. The overall prevalence of Helicobacter pylori was 66% in the study and 53.5% in the control group. The CagA seroprevalence was 38.3% in the study and 21% in the control group, with no significant difference. A significant correlation was noted between differentiation of tumor and CagA seropositivity among Helicobacter pylori–infected patients. The remaining parameters did not show any association with either H. pylori or CagA strain. This study showed no association between Helicobacter pylori infection and colorectal cancers. However, a correlation between CagA strains with well-differentiated adenocarcinoma in Helicobacter pylori–infected patients was noted. Clinical Trial Registration Number: CTRI/2018/01/011607.
Fully abstract models for effectful λ-calculi via category-theoretic logical relations

We present a construction which, under suitable assumptions, takes a model of Moggi’s computational λ-calculus with sum types, effect operations and primitives, and yields a model that is adequate and fully abstract. The construction, which uses the theory of fibrations, categorical glueing, ⊤⊤-lifting, and ⊤⊤-closure, takes inspiration from O’Hearn & Riecke’s fully abstract model for PCF. Our construction can be applied in the category of sets and functions, as well as the category of diffeological spaces and smooth maps and the category of quasi-Borel spaces, which have been studied as semantics for differentiable and probabilistic programming.
Assessment of gender inequality in education : A survey of women in the administrative cadre of selected tertiary institutions in Rivers State , Nigeria .

This study investigated gender inequality in education. Specifically, it x-rayed the proportion and rationale behind gender inequality with emphasis to women in the administrative cadre of tertiary institutions in Rivers State, Nigeria. Descriptive survey research design was adopted and used for the study. The population consisted of female in the administrative cadre of three tertiary institutions in Rivers State, namely: Rives State University of Science and Technology (RSUST) now Rivers State University, Ignatius Ajuru University of Education (IAUOE), and Rivers State Polytechnic Bori (RIVPOLY). The women population were 128 in the three institutions. The instrument for data collection was a questionnaire titled “Gender inequality in education questionnaire” (GIEQ). The researcher used proportionate stratified random sampling to obtain a population of 120; meaning 40 women were selected from each of the institutions. One hundred and twenty (120) copies of the questionnaire were distributed but 115 were retrieved and found useful for analysis. Five research questions were raised and answered in this study. The research questions were analysed using frequency counts, mean and standard deviation. The results of the analyses revealed that gender inequality is prevalent in administrative offices, heads of offices give excuses for not appointing women in administrative positions, women are not denied positions in the administrative cadre when they merit them, that male domination lead to gender inequality and that domestic work affects gender equality in administrative offices. It was concluded that women in administration and in other sectors should be treated fairly since the society cannot grow without their contributions. Among others, it was recommended that government, private and NGOs should ensure gender equality when employing or appointing staff in their offices so as to encourage women to showcase their potentials and contribute meaningfully to the development of the society.