Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential effects of pre-mRNA splicing inhibitors on RNA polymerase II transcription

Summary The production of eukaryotic mRNA requires transcription by RNA polymerase (pol) II and co-transcriptional processing, including capping, splicing, and cleavage and polyadenylation (CPA). Pol II can positively affect co-transcriptional processing through interaction of factors with its carboxyl terminal domain (CTD), comprising 52 repeats of the heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Small molecule inhibitors of the splicing factor SF3B1 cause loss of the transcription elongation factor P-TEFb from protein-coding gene templates and major transcription defects, indicating that splicing can, in turn, positively affect transcription. To understand better the relationship between pre-mRNA splicing and pol II transcription, we have investigated the effect of two other splicing inhibitors, Madrasin and Isoginkgetin, on transcription. We found that Madrasin rapidly inhibits pre-mRNA splicing, whereas Isoginkgetin affects transcription before any detectable effect on pre-mRNA splicing. Interestingly, we found that both of these small molecules promote general downregulation of transcription and global transcriptional readthrough, including on intronless and histone genes. Both small molecules affect the association of the mRNA CPA complex with chromatin, likely explaining the transcription termination defect. However, splicing inhibition is not necessarily associated with transcriptional readthrough as small molecule inhibitors of SF3B1 or knockdown of splicing factors do not cause a global transcription termination defect.
Compensatory adaptation does not fully alleviate the costs associated with rifampicin resistance and occurs predominantly through off-target mutations

The manner in which costs associated with antibiotic resistance mutations are alleviated through the acquisition of compensatory mutations has bearing on the dynamics of resistance accumulation and spread as well as on our more general understanding of the persistence of adaptive genotypes. Here, we combine evolutionary experiments, fitness analyses, and whole genome sequencing to examine the way compensation to alleviate costs associated with rifampicin resistance is achieved, both when resistance is fixed and when initial majorities of resistant cells are grown alongside susceptible cells. We found compensatory mutations to occur across all examined populations. However, compensation never fully alleviates the initial costs of resistance. In contrast to prevalent assumptions, compensatory mutations mostly occurred outside of the RNA polymerase core enzyme, which serves as the target of rifampicin. The target size for compensatory mutations appears to be high, as great variation exists in compensatory mutations, even within a single population. At the same time, the pathways of compensation are quite convergent, meaning that, across independent populations, we often observe compensatory mutations in the same loci and sometimes even observe the precise same compensatory mutations across populations.
Apoptosis recognition receptors regulate skin tissue repair in mice

Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1+ macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for apoptotic genes and display increased and altered efferocytosis signaling via the receptor Axl. During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studies in vivo in mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.
Manifold Learning for fMRI time-varying FC

Whole-brain functional connectivity (FC) measured with functional MRI (fMRI) evolve over time in meaningful ways at temporal scales going from years (e.g., development) to seconds (e.g., within-scan time-varying FC (tvFC)). Yet, our ability to explore tvFC is severely constrained by its large dimensionality (several thousands). To overcome this difficulty, researchers seek to generate low dimensional representations (e.g., 2D and 3D scatter plots) expected to retain its most informative aspects (e.g., relationships to behavior, disease progression). Limited prior empirical work suggests that manifold learning techniques (MLTs)—namely those seeking to infer a low dimensional non-linear surface (i.e., the manifold) where most of the data lies—are good candidates for accomplishing this task. Here we explore this possibility in detail. First, we discuss why one should expect tvFC data to lie on a low dimensional manifold. Second, we estimate what is the intrinsic dimension (i.e., minimum number of latent dimensions; ID) of tvFC data manifolds. Third, we describe the inner workings of three state-of-the-art MLTs: Laplacian Eigenmaps (LE), T-distributed Stochastic Neighbor Embedding (T-SNE), and Uniform Manifold Approximation and Projection (UMAP). For each method, we empirically evaluate its ability to generate neuro-biologically meaningful representations of tvFC data, as well as their robustness against hyper-parameter selection. Our results show that tvFC data has an ID that ranges between 4 and 26, and that ID varies significantly between rest and task states. We also show how all three methods can effectively capture subject identity and task being performed: UMAP and T-SNE can capture these two levels of detail concurrently, but LE could only capture one at a time. We observed substantial variability in embedding quality across MLTs, and within-MLT as a function of hyper-parameter selection. To help alleviate this issue, we provide heuristics that can inform future studies. Finally, we also demonstrate the importance of feature normalization when combining data across subjects and the role that temporal autocorrelation plays in the application of MLTs to tvFC data. Overall, we conclude that while MLTs can be useful to generate summary views of labeled tvFC data, their application to unlabeled data such as resting-state remains challenging.
EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption upon Pseudomonas infection

The intracellular inflammasome complex have been implicated in the maladaptive tissue damage and inflammation observed in chronic Pseudomonas aeruginosa infection. Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by P. aeruginosa, specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that the NLRP1 inflammasome detects Exotoxin A (EXOA), a ribotoxin released by P. aeruginosa Type 2 Secretion System (T2SS) during chronic infection. Mechanistically, EXOA-driven Eukaryotic Elongation Factor 2 (EEF2) ribosylation and covalent inactivation promotes ribotoxic stress and subsequent NLRP1 inflammasome activation, a process shared with other EEF2-inactivating toxins, Diphtheria Toxin and Cholix Toxin. Biochemically, irreversible EEF2 inactivation triggers ribosome stress-associated kinases ZAKα- and P38-dependent NLRP1 phosphorylation and subsequent proteasome-driven functional degradation. Finally, Cystic Fibrosis cells from patients exhibit exacerbated P38 activity and hypersensitivity to EXOA-induced ribotoxic stress-dependent NLRP1 inflammasome activation, a process inhibited by the use of ZAKα inhibitors. Altogether, our results show the importance of P. aeruginosa virulence factor EXOA at promoting NLRP1-dependent epithelial damage and identify ZAKα as a critical sensor of virulence-inactivated EEF2. KEY POINTS P. aeruginosa induces NLRP1-dependent pyroptosis in human corneal and nasal epithelial cells P. aeruginosa Exotoxin A (EXOA) and other EEF2-inactivating bacterial exotoxins activate the human NLRP1 inflammasome EEF2 inactivation promotes ribotoxic stress response and ZAKα kinase-dependent NLRP1 inflammasome activation. Bronchial epithelial cells from Cystic Fibrosis patients show extreme sensitivity to ribotoxic stress-dependent NLRP1 inflammasome activation in response to Exotoxin A P38 and ZAKα inhibition protects Cystic Fibrosis epithelial cell from EXOA-induced pyroptosis
Human Tissues Exhibit Diverse Composition of Translation Machinery

While protein synthesis is vital for the majority of cell types of the human body, diversely differentiated cells require specific translation regulation. This suggests specialization of translation machinery across tissues and organs. Using transcriptomic data from GTEx, FANTOM, and Gene Atlas we systematically explored the abundance of transcripts encoding translation factors and aminoacyl-tRNA synthetases (ARSases) in human tissues. We revised a few known and identified several novel translation-related genes exhibiting strict tissue-specific expression. The proteins they encode include eEF1A1, eEF1A2, PABPC1L, PABPC3, eIF1B, eIF4E1B, eIF4ENIF1, and eIF5AL1. Furthermore, our analysis revealed a pervasive tissue-specific relative abundance of translation machinery components (e.g. PABP and eRF3 paralogs, eIF2B subunits, eIF5MPs, and some ARSases), suggesting presumptive variance in the composition of translation initiation, elongation, and termination complexes. These conclusions were largely confirmed by the analysis of proteomic data. Finally, we paid attention to sexual dimorphism in the repertoire of translation factors encoded in sex chromosomes (eIF1A, eIF2γ, and DDX3), and identified testis and brain as organs with the most diverged expression of translation-associated genes.
Shared patterns of population genomic variation and phenotypic response across rapid range expansions in two invasive lady beetle species

Non-native lady beetle species have often been introduced, with variable success, into North America for biological control of aphids, scales, whiteflies, and other agricultural pests. Two predatory lady beetle species, Propylea quatuordecimpunctata and Hippodamia variegata, both originating from Eurasia, were first discovered near Montreal, Quebec, in North America in 1968 and 1984, respectively, and have since expanded into northeastern North America and the midwestern United States. In this study, we estimate the range-wide population structure, establishment and range-expansion, and recent evolutionary history of these species of non-native lady beetles using reduced representation genotyping-by-sequencing via ddRADseq. In addition, we quantified the responses to a key abiotic factor, photoperiod, that regulates adult reproductive diapause in these two species and may influence their latitudinal distribution and spread in North America. Our analyses detect (1) non-significant genetic differentiation and divergence among North American populations, (2) evidence of reduced contemporary gene flow within the continental US, (3) significant phenotypic differences in diapause induction despite genetic similarities across sampled populations.
Brewster Angle Phenomenon in Two-Dimensional Metallic Photonic Crystals and its Application to Polarization Beam Splitting

The authors show the Brewster angle phenomenon of p waves in two-dimensional metallic photonic crystals of rectangular lattices with effective medium theory and accurate multiple-scattering calculations. The Brewster angle can be tuned over a wide range by varying the structure parameters. Based on this phenomenon, the authors propose a polarization beam splitter which can completely separate the p and s waves at an incident angle of 45°±10° in a very wide wavelength range (1∼500μm).
Extraordinary Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, CH.1.1 and CA.3.1 Variants

Newly emerging Omicron subvariants continue to emerge around the world, presenting potential challenges to current vaccination strategies. This study investigates the extent of neutralizing antibody escape by new subvariants XBB.1. 5, CH.1. 1, and CA.3. 1, as well as their impacts on spike protein biology. Our results demonstrated a nearly complete escape of these variants from neutralizing antibodies stimulated by three doses of mRNA vaccine, but neutralization was rescued by a bivalent booster. However, CH.1. 1 and CA.3. 1 variants were highly resistant to both monovalent and bivalent mRNA vaccinations. We also assessed neutralization by sera from individuals infected during the BA.4/5 wave of infection and observed similar trends of immune escape. In these cohorts, XBB.1. 5 did not exhibit enhanced neutralization resistance over the recently dominant BQ.1. 1 variant. Notably, the spike proteins of XBB.1. 5, CH.1. 1, and CA.3. 1 all exhibited increased fusogenicity compared to BA.2, correlating with enhanced S processing. Overall, our results support the administration of new bivalent mRNA vaccines, especially in fighting against newly emerged Omicron subvariants, as well as the need for continued surveillance of Omicron subvariants.
Experiences from Learnersourcing SQL Exercises: Do They Cover Course Topics and Do Students Use Them?

Learnersourcing is an emerging phenomenon in computing education research and practice. In learnersourcing, a crowd of students participates in the creation of course resources such as exercises, written materials, educational videos, and so on. In computing education research, learnersourcing has been studied especially for the creation of multiple-choice questions and programming exercises, where prior work has suggested that learnersourcing can have multiple benefits for teachers and students alike. One result in prior studies is that when students create learnersourced content, the created content covers much of the learning objectives of the course. The present work expands on this stream of work by studying the use of a learnersourcing system in the context of teaching SQL. We study to what extent learnersourced SQL exercises cover course topics, and to what extent students complete learnersourced exercises. Our results continue the parade of previous learnersourcing studies, empirically demonstrating that learnersourced content covers instructor-specified course topics and that students indeed actively work on the learnersourced exercises. We discuss the impact of these results on teaching with learnersourcing, highlight possible explanations for our observations, and outline directions for future research on learnersourcing.
Antineoplastic multi-drug chemotherapy to sensitize tumors triggers multi-drug resistance and inhibits efficiency of maintenance treatment inglioblastoma cells

Combinations of the well-known antineoplastic agents 5-fluorouracil (5-Fu), cisplatin, and paclitaxel are employed to increase radiotherapy/immunotherapy efficacy against persistent and resistant tumors. However, data remains needed on the hormetic, chronic, and long-term side effects of these aggressive combination chemotherapies. Here we investigated cellular and molecular responses associated with these combined agents, and their potential to induce multi-drug resistance against the temozolomide (TMZ) and etoposide (EP) used in glioblastoma maintenance treatment. We analyzed resistance and survival signals in U87 MG cells using molecular probes, fluorescent staining, qRT-PCR, and immunoblot. Repeated treatment with combined 5-Fu, cisplatin, and paclitaxel induced cross-resistance against TMZ and EP. Resistant cells exhibited elevated gene/protein expression of MRP1/ABCC1, ABCC2, BRCP/ABCG2, and GST. Moreover, they managed oxidative stress, cell cycle, apoptosis, and autophagy signaling to ensure survival. In these groups TMZ and etoposide efficiency dramatically reduced. Our result suggests that combined high-dose treatments of classical antineoplastic agents to sensitize tumors may trigger multi-drug resistance and inhibit maintenance treatment. When deciding on antineoplastic combination therapy for persistent/resistant glioblastoma, we recommend analyzing the long-term hormetic and chronic effects on cross-resistance and multi-drug resistance in primary cell cultures from patients. See also the Graphical Abstract(Fig. 1).
Streaming Potential and Hydraulic Permeation Through Cation-Exchange Membranes

The streaming potential and the hydraulic permeation were obtained, under different experimental conditions, for a cation-exchange membrane. From the measurements we have determined the phenomenological coefficients, Ltj, that enter the equations describing electrokinetic phenomena according to the Thermodynamics of Irreversible Processes. The results obtained for the streaming potential are correlated to the results obtained for electroosmosis, under the same experimental conditions, in a previous paper. It permits us to state that Onsager's reciprocity relation holds up to 10 ~ mol/liter KC1 concentration. The effective fixed charge concentration was estimated from the results of the streaming potential, hydraulic permeation and resistance of the membrane.
The forces on a cylinder in a stream of viscous fluid

It has long been known that an infinite cylinder moving transversely with uniform velocity in a perfect liquid, or at rest in a uniform stream of such fluid, experiences no resistance if there be no circulation round the cylinder. The corresponding theorem in the case where circulation exists is due to W. M. Kutta and N. Joukowski, and is generally known as the Kutta-Joukowski theorem. If the velocity of the cylinder is U, there is a force transverse to the direction of motion, of amount ρUI, where I is the circulation round the cylinder and ρ the density of the fluid. This result forms the basis of the modern theory of aeroplane lift, developed in the first instance by Lanchesteri and later by Prandtl. In this theory, however, it is assumed that, at a comparatively small distance from the surface of the cylinder, the motion is strictly irrotational, and is, therefore, given by the equations which hold in a perfect fluid, the vortex motion, which involves viscosity, being limited to a “boundary layer” in the immediate neighbourhood of the cylinder and to a “wake” of which the effect is neglected after it leaves the immediate vicinity of the body.
Associated factors of pelvic organ prolapse among patients at Public Hospitals of Southern Ethiopia: A case-control study design

Background Pelvic organ prolapse (POP) is the descent of the vaginal wall, cervix, uterus, bladder, and rectum downward into the vaginal canal. It occurs owing to the weakness of the structures supporting and keeping pelvic organs in anatomic position. Prolapse occurs due to exposure to risk factors; women in developing countries are highly predisposed to the risk factors of the prolapse. No study assesses POP in Southern Ethiopia. Methods A case-control study design was employed in 369 participants (123 cases and 246 controls) of seven randomly selected Public Hospitals of Southern Ethiopia from February-June, 2020, using a structured questionnaire. All patients diagnosed with prolapse (stage I- IV) were included as cases; patients free of prolapse (stage 0) were taken as controls after physicians had performed a diagnosis and vaginal examination. Bivariate and multivariable logistic regression analyses were performed using SPSS. Results In this study, after adjusting for covariates, age of the women ≥ 45 years (AOR = 5.33, 95% CI: 1.47, 9.05), underweight (AOR= 4.54, 95% CI: 1.4, 15.76), low income (AOR = 2.5, 95% CI:1.14, 5.59), parity ≥5 (AOR = 5.2, 95% CI: 2.2, 12.55), assisted vaginal delivery (AOR= 4, 95% CI: 1.55, 11.63), instrumental delivery (AOR= 3.5, 95% CI:1.45, 84), sphincter damage and vaginal tear (AOR = 3.2, 95% CI:1.44,7.1), carrying heavy loads (AOR= 2.5, 95% CI:1.2, 5.35), and prolonged labor ≥24 hours (AOR = 3.3, 95% CI:1.12, 97) were significant associated factors of prolapse. The odds of developing prolapse is lower among women attended school. Most(84.55%) of the women with prolapse were delayed for the treatments and only surgical interventions were done as treatments. Most of them claimed lack of social support, lack of money, and social stigma as the main reasons for the delay in seeking treatments. Conclusions Older age, low educational status, underweight, low income, higher parity, assisted vaginal delivery, prolonged labor, sphincter damage, and carrying heavy loads were significant associated factors of POP. It is better to screen older age women by doing campaigns against the prolapse. Also, responsible bodies should work on raising awareness of women as well as awareness of the community about the prolapse through expanding health education. Moreover, informing women to practice pelvic muscle training daily, raising women’s income to empower them, and help of family members to reduce carrying an overload of mothers are recommended.
The Relative Risk of Toxico-Clinical Parameters with respect to Poisoning Severity and Outcomes in Patients with Acute Poisoning

Background: Complications or death risk factors is necessary for better monitoring and treatment. The aim of this study was to define the relative risk of toxico-clinical parameters with regard to poisoning severity and outcomes in patients with acute poisoning. Materials and Methods: This cross-sectional study entailed of patients with acute poisoning admitted to the poisoning emergency center of khorshid hospital, Isfahan, Iran from December 2018 until March 2019. Patients (n = 300) were categorized into four groups (minor, moderate, severe, and fatal poisoning) based on severity. Multivariate logistic regression analysis was employed to calculate the odds ratio (OR) as the estimate of the relative risk of the different variables for the poisoning severity and outcomes prediction. Results: In the minor group, opioids/opiates, alcohols, and benzodiazepines (14.7%) were the most prevalent poisoning, multidrug (23.3%) was in the moderate and severe groups and finally, pesticides poisoning (23%) was most common in the fatal group. The predictive factors for poisoning severity were pre-hospital antidote administration [OR, (95%CI); P value) [7.08 (1.77-28.34); 0.006]; loss of consciousness [4.38 (1.84-10.42), 0.001]; abnormal ECG [4.56 (1.65-12.56); 0.003]; and time interval of poisoning to admission in the hospital [1.15 (1.02-1.28); 0.01). Patients without complications was observed in 49.7% of subjects. Patients with the loss of consciousness [66.06 (2.41-180.07); 0.01); underlying disease [3.65 (1.09-12.24); 0.03]; abnormal respiration [1.14 (1.02-1.27); 0.02); have had a greater risk of complications and death. Conclusion: Important factors for poisoning severity and/or outcome were loss of consciousness, pre-hospital antidote administration, abnormal ECG or respiration, underlying disease, and delay to presentation to hospital.