Miracle-dz/UniFAR-FTUs huggingface dataset:
RNase HIII Is Important for Okazaki Fragment Processing in Bacillus subtilis

All cells are required to resolve the different types of RNA-DNA hybrids that form in vivo. When RNA-DNA hybrids persist, cells experience an increase in mutation rate and problems with DNA replication. Okazaki fragment synthesis on the lagging strand requires an RNA primer to begin synthesis of each fragment. The mechanism of RNA removal from Okazaki fragments remains unknown in bacteria that lack RNase HI. We examined Okazaki fragment processing in vitro and found that RNase HIII in conjunction with DNA polymerase I represent the most efficient repair pathway. We also assessed the contribution of YpcP and found that YpcP is a 5′ to 3′ exonuclease that prefers RNA substrates with activity on Okazaki and flap substrates in vitro. ABSTRACT RNA-DNA hybrids are common in chromosomal DNA. Persistent RNA-DNA hybrids result in replication fork stress, DNA breaks, and neurological disorders in humans. During replication, Okazaki fragment synthesis relies on frequent RNA primer placement, providing one of the most prominent forms of covalent RNA-DNA strands in vivo. The mechanism of Okazaki fragment maturation, which involves RNA removal and subsequent DNA replacement, in bacteria lacking RNase HI remains unclear. In this work, we reconstituted repair of a linear model Okazaki fragment in vitro using purified recombinant enzymes from Bacillus subtilis. We showed that RNase HII and HIII are capable of incision on Okazaki fragments in vitro and that both enzymes show mild stimulation by single-stranded DNA binding protein (SSB). We also showed that RNase HIII and DNA polymerase I provide the primary pathway for Okazaki fragment maturation in vitro. Furthermore, we found that YpcP is a 5′ to 3′ nuclease that can act on a wide variety of RNA- and DNA-containing substrates and exhibits preference for degrading RNA in model Okazaki fragments. Together, our data showed that RNase HIII and DNA polymerase I provide the primary pathway for Okazaki fragment maturation, whereas YpcP also contributes to the removal of RNA from an Okazaki fragment in vitro. IMPORTANCE All cells are required to resolve the different types of RNA-DNA hybrids that form in vivo. When RNA-DNA hybrids persist, cells experience an increase in mutation rate and problems with DNA replication. Okazaki fragment synthesis on the lagging strand requires an RNA primer to begin synthesis of each fragment. The mechanism of RNA removal from Okazaki fragments remains unknown in bacteria that lack RNase HI. We examined Okazaki fragment processing in vitro and found that RNase HIII in conjunction with DNA polymerase I represent the most efficient repair pathway. We also assessed the contribution of YpcP and found that YpcP is a 5′ to 3′ exonuclease that prefers RNA substrates with activity on Okazaki and flap substrates in vitro.
Evaluating an Oral Health Education Intervention in Chinese Undocumented Migrant Mothers of Infants in Northern Ireland

Background: Poor oral health remains a significant dental public health challenge for ethnic minority and immigrant groups living in the UK. This study aimed to evaluate a culturally appropriate community-based home visiting oral health education intervention for Chinese, undocumented migrant mothers to promote their infants’ oral health, by focusing on their oral health related knowledge, attitudes, and behaviors. Methods: A convenience sample of 36 Chinese mothers with babies aged less than eight weeks were recruited in South-East region of Belfast. The local Chinese community was consulted to assist with the development of the intervention. The oral health education intervention was provided to 19 intervention group mothers through home visits and telephone calls during mothers’ first postpartum year. They were also provided with unlimited social support during the intervention period. Mothers’ oral health related knowledge, attitudes, and behaviors regarding baby toothbrushing and sugar snacking were measured at eight weeks, six months, and 12 months. Results: A higher proportion of Chinese intervention group mothers had improved knowledge about baby toothbrushing at 12 months compared with control group mothers (χ2 = 14.12: p = 0.004). Significantly, more intervention group mothers’ oral health related attitudes were enhanced regarding baby toothbrushing and sugar snacking compared with control group mothers. Conclusion: This community-based oral health education intervention has shown effects in mothers’ self-reported knowledge, attitudes, and behaviors in the intervention group when the community based and culturally appropriate home-visiting program improved the mothers’ oral health related knowledge, attitudes, and behaviors.
Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer

Analysis of adaptive kinome activity reveals paths of drug resistance in HER2-positive breast cancer. Blocking drug resistance The identification of “cancer drivers” enables the development of targeted therapeutics, but tumors often exhibit—or inevitably develop—resistance to these drugs. Knowing how tumors do this is essential for better and more durable clinical outcomes in patients. Using a multiomics approach, Schwill et al. studied the activities of kinase networks in HER2-positive breast cancer cells in response to HER2-targeted drugs. From these networks, they identified critical proteins, such as the kinase FAK1, that enabled sustained cell survival. Combining an FAK1 inhibitor with a HER2-blocking agent synergistically induced cell death. These findings may inform the development of more effective combination therapies for patients with HER2-positive breast cancer. Drug-induced compensatory signaling and subsequent rewiring of the signaling pathways that support cell proliferation and survival promote the development of acquired drug resistance in tumors. Here, we sought to analyze the adaptive kinase response in cancer cells after distinct treatment with agents targeting human epidermal growth factor receptor 2 (HER2), specifically those that induce either only temporary cell cycle arrest or, alternatively, apoptosis in HER2-overexpressing cancers. We compared trastuzumab, ARRY380, the combination thereof, and a biparatopic, HER2-targeted designed ankyrin repeat protein (DARPin; specifically, 6L1G) and quantified the phosphoproteome by isobaric tagging using tandem mass tag liquid chromatography/tandem mass spectrometry (TMT LC-MS/MS). We found a specific signature of persistently phosphorylated tyrosine peptides after the nonapoptotic treatments, which we used to distinguish between different treatment-induced cancer cell fates. Next, we analyzed the activation of serine/threonine and tyrosine kinases after treatment using a bait peptide chip array and predicted the corresponding active kinases. Through a combined system-wide analysis, we identified a common adaptive kinase response program that involved the activation of focal adhesion kinase 1 (FAK1), protein kinase C-δ (PRKCD), and Ephrin (EPH) family receptors. These findings reveal potential targets to prevent adaptive resistance to HER2-targeted therapies.
New Phylogenomic Analysis of the Enigmatic Phylum Telonemia Further Resolves the Eukaryote Tree of Life

The broad-scale tree of eukaryotes is constantly improving, but the evolutionary origin of several major groups remains unknown. Resolving the phylogenetic position of these ‘orphan’ groups is important, especially those that originated early in evolution, because they represent missing evolutionary links between established groups. Telonemia is one such orphan taxon for which little is known. The group is composed of molecularly diverse biflagellated protists, often prevalent although not abundant in aquatic environments. Telonemia has been hypothesized to represent a deeply diverging eukaryotic phylum but no consensus exists as to where it is placed in the tree. Here, we established cultures and report the phylogenomic analyses of three new transcriptome datasets for divergent telonemid lineages. All our phylogenetic reconstructions, based on 248 genes and using site-heterogeneous mixture models, robustly resolve the evolutionary origin of Telonemia as sister to the Sar supergroup. This grouping remains well supported when as few as 60% of the genes are randomly subsampled, thus is not sensitive to the sets of genes used but requires a minimal alignment length to recover enough phylogenetic signal. Telonemia occupies a crucial position in the tree to examine the origin of Sar, one of the most lineage-rich eukaryote supergroups. We propose the moniker ‘TSAR’ to accommodate this new mega-assemblage in the phylogeny of eukaryotes.
Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.
Emotions and coping methods of Turkish parents of children with cancer

Abstract Objective: This hermeneutic phenomenological study was conducted with the aim to determine the emotions and coping methods of Turkish parents whose children were diagnosed with cancer. Methods: Data were collected through in-person, in-depth interviews with 12 parents (8 mothers, 4 fathers). The semi-structured interview form was developed based on Elisabeth Kübler-Ross's model of the five stages of grief (denial, anger, bargaining, depression and acceptance) with the addition of questions on coping methods. Data interpretation proceeded through three phases: superficial reading, structural analysis and comprehensive understanding. Results: All the parents made statements indicating their devastation while expressing their feelings at the moment they learned of the diagnosis. After overcoming the first shock, most thought it was a false diagnosis, and some thought it was a test from God. The parents were angry mostly with the doctors, themselves, their spouses and God. All the parents participating in the study stated that they had regrets about the past. Most engaged in more emotion-oriented and fewer problem-focused coping efforts. However, some parents used negative coping methods. Conclusion: These parents need help from healthcare professionals to come to terms with their grief.
The Cu/Zn superoxide dismutase +35A/C (rs2234694) variant correlates with altered levels of protein carbonyls and glutathione and associates with severity of COPD in a Tunisian population

Abstract Chronic obstructive pulmonary disease (COPD) is a major cause of mortality that has been associated with inflammation and oxidative stress. The purpose of the present case–control study was to determine the relationships between oxidative stress-related genetic variants and the risk and severity of COPD, as well as, the influence of these variants on inflammatory and oxidative stress parameters. Genotyping of superoxide dismutase 1 (SOD1) + 35 A/C (rs2234694), catalase [A-21T (rs7943316), C-262T (rs1001179)] and glutathione peroxidase 1 (reduced glutathione (GSH)-Px1) 198Pro/Leu (rs1050450) was carried out in 143 patients with COPD and 216 healthy controls using PCR-RFLP. Serum levels of IL-6 and TNF-α were determined by enzyme-linked immunosorbent assays (ELISA), while the levels of reduced GSH, total antioxidant status (TAS), H2O2, lipid peroxides (TBARS) and protein carbonyls (PCs) were determined using spectrophotometric methods. We also evaluated the activities of GSH-Px, catalase, and superoxide dismutase (SOD) in both plasma and erythrocytes. We did not observe significant differences in the genotype and allele frequencies of chosen variants between COPD patients and healthy controls. A significant correlation was retrieved between the SOD1 + 35A/C variant and disease severity (odds ratios (OR) = 0.15, p = 0.04). In addition, patients having the +35AC genotype presented increased plasma levels of GSH and a reduced level of PCs (p = 0.03, p = 0.04, respectively). The present data highlighted the important role of antioxidant enzymes and their genetic variants in the oxidative stress-mediated pathogenesis and progression of COPD.
Efficacy of Intranasal Administration of the Recombinant Endolysin SAL200 in a Lethal Murine Staphylococcus aureus Pneumonia Model

SAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model. ABSTRACT SAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model. Lethal pneumonia was established by intranasally administering a methicillin-susceptible (Newman) or methicillin-resistant (LAC) S. aureus strain into BALB/c mice. The mice were treated with a single intranasal administration of SAL200 or phosphate-buffered saline at 2 h after S. aureus infection. The survival rates were recorded until 60 h after the bacterial challenge. The bacterial loads in the lungs and blood, histopathology of lung tissues, and serum cytokine levels were evaluated following the S. aureus challenge. The SAL200-treated group and control group exhibited 90% to 95% and 10% to 40% survival rates, respectively. The bacterial loads in the lungs of the SAL200-treated group were significantly lower by ∼10-fold than those of the control group as early as 1 h after treatment. Histopathologic recovery of pneumonia was observed in the SAL200-treated mice. The cytokine levels were comparable between groups. These results suggest that direct administration of SAL200 into the lungs could be a potential adjunct treatment against severe pneumonia caused by S. aureus.
Choroidal thickness in normal Indian eyes using swept-source optical coherence tomography

Purpose: The purpose of this study is to provide normative database for subfoveal choroidal thickness in Indian eyes using swept-source optical coherence tomography. Methods: This is a cross-sectional study based at a tertiary eye care center in Northern India. Two hundred and thirty eight eyes of 119 healthy subjects were examined in terms of axial length, spherical equivalent, and choroidal thickness. Inclusion criteria included age 19–60 years, no retinal or choroidal disorder, and patients with clear media and good fixation. Patients with high hypermetropia (>4 D) or myopia (>6 D) or any systemic disease likely to affect choroidal thickness were excluded. Twelve radial line scans were obtained centered on the fovea that were used to calculate choroidal and retinal thickness in 9 early treatment diabetic retinopathy study (ETDRS) zones. Results: The mean age of all the subjects was 28.70 ± 11.28 years; mean axial length was 23.63 ± 1.96 mm, and mean spherical equivalent was − 0.92 ± 3.08 D. The mean subfoveal choroidal thickness was 299.10 ± 131.2 μ and mean foveal thickness was 239.92 ± 48.16 μ. A negative correlation was found between subfoveal choroidal thickness and age (r = −0.0961, P = 0.1392) and axial length (r = −0.3166, P < 0.001). A statistically significant positive correlation was found between subfoveal choroidal thickness and refractive error (r = 0.2393, P = 0.0002). Conclusion: This study provides normative database for subfoveal choroidal thickness and foveal thickness using swept-source optical coherence tomography. The choroidal thickness measured with swept-source platform is slightly higher than that reported with spectral domain platforms.
No Differences in Weight Gain Between Risperidone and Aripiprazole in Children and Adolescents After 12 Months.

BACKGROUND Weight gain due to the use of second-generation antipsychotics is a major health care issue for adult and paediatric psychiatric patients. Little is known about long-term weight gain effects of aripiprazole compared to risperidone in children and adolescents. OBJECTIVE The primary aim of this study is to assess whether risperidone and aripiprazole are associated with different weight changes in children and adolescents during the first 12 months of treatment. Secondary aim was to assess the influence of the covariates co-medication, gender and indication on weight change. METHODS This study was a retrospective observational cohort study of in- and outpatients of a Dutch mental health organization aged ≤19 years on long-term treatment with risperidone or aripiprazole. Primary outcome measure was body-mass index (BMI) z-score change. Data were extracted from medical charts and analysed using linear mixed models. RESULTS In total, 89 risperidone patients and 42 aripiprazole patients were included in the study. At baseline, the BMI z-score of aripiprazole subjects was significantly higher than risperidone subjects (p = 0.003). In both treatment groups BMI z-score significantly increased during 12 months of follow-up. This weight change was not significantly different in risperidone and aripiprazole users after 12 months (p = 0.943). Covariates did not significantly influence weight change. CONCLUSION This study demonstrated that there was no significant difference in weight gain between risperidone and aripiprazole users during the first year of treatment. Based on this study, aripiprazole should not be favoured over risperidone in children and adolescents because of the degree of weight gain.
The smoking behaviors of incarcerated smokers

To determine smoking behaviors, quit attempts, and cessation preferences among incarcerated smokers, a cross-sectional survey was given to a sample of inmates from three state prison facilities in the United States. A majority of Black smokers (62%) identified as smokers, and 38% identified as ex-smokers, as compared to 46.4 percent of smokers (and 53.6% of ex-smokers) in the non-Black group. There were significant differences in the number of cigarettes smoked per day with non-Black smokers smoking one pack (M = 20.44, standard deviation = 15.86) than Black smokers (M = 14.49, standard deviation = 13.43; t = −2.50, p = 0.014). Smoking cessation interventions are needed to reduce smoking during incarceration.
Endothelin-1 stimulates expression of cyclin D1 and S-phase kinase–associated protein 2 by activating the transcription factor STAT3 in cultured rat astrocytes

Brain injury–mediated induction of reactive astrocytes often leads to glial scar formation in damaged brain regions. Activation of signal transducer and activator of transcription 3 (STAT3), a member of the STAT family of transcription factors, plays a pivotal role in inducing reactive astrocytes and glial scar formation. Endothelin-1 (ET-1) is a vasoconstrictor peptide, and its levels increase in brain disorders and promote astrocytic proliferation through ETB receptors. To clarify the mechanisms underlying ET-1–mediated astrocytic proliferation, here we examined its effects on STAT3 in cultured rat astrocytes. ET-1 treatment stimulated Ser-727 phosphorylation of STAT3 in the astrocytes, but Tyr-705 phosphorylation was unaffected, and ET-induced STAT3 Ser-727 phosphorylation was reduced by the ETB antagonist BQ788. ET-1 stimulated STAT3 binding to its consensus DNA-binding motifs. Monitoring G1/S phase cell cycle transition through bromodeoxyuridine (BrdU) incorporation, we found that ET-1 increases BrdU incorporation into the astrocytic nucleus, indicating cell cycle progression. Of note, STAT3 chemical inhibition (with stattic or 5,15-diphenyl-porphine (5,15-DPP)) or siRNA-mediated STAT3 silencing reduced ET-induced BrdU incorporation. Moreover, ET-1 increased astrocytic expression levels of cyclin D1 and S-phase kinase-associated protein 2 (SKP2), which were reduced by stattic, 5,15-DPP, and STAT3 siRNA. ChIP-based PCR analysis revealed that ET-1 promotes the binding of SAT3 to the 5′-flanking regions of rat cyclin D1 and SKP2 genes. Our results suggest that STAT3-mediated regulation of cyclin D1 and SKP2 expression underlies ET-induced astrocytic proliferation.
A Selective Review of Multi-Level Omics Data Integration Using Variable Selection

High-throughput technologies have been used to generate a large amount of omics data. In the past, single-level analysis has been extensively conducted where the omics measurements at different levels, including mRNA, microRNA, CNV and DNA methylation, are analyzed separately. As the molecular complexity of disease etiology exists at all different levels, integrative analysis offers an effective way to borrow strength across multi-level omics data and can be more powerful than single level analysis. In this article, we focus on reviewing existing multi-omics integration studies by paying special attention to variable selection methods. We first summarize published reviews on integrating multi-level omics data. Next, after a brief overview on variable selection methods, we review existing supervised, semi-supervised and unsupervised integrative analyses within parallel and hierarchical integration studies, respectively. The strength and limitations of the methods are discussed in detail. No existing integration method can dominate the rest. The computation aspects are also investigated. The review concludes with possible limitations and future directions for multi-level omics data integration.