Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterization of the first microRNA in human CDH1 that affects cell cycle and apoptosis and indicates breast cancers progression

The E‐cadherin protein (Cadherin 1, gene: CDH1), a master regulator of the human epithelial homeostasis, contributes to the epithelial‐mesenchymal transition (EMT) which confers cell migratory features to the cells. The EMT is central to many pathophysiological changes in cancer. Therefore, a better understanding of this regulatory scenario is beneficial for therapeutic regiments. The CDH1 gene is approximately 100 kbp long and consists of 16 exons with a relatively large second intron. Since none microRNA (miRNA) has been identified in CDH1 up to now we screened the CDH1 gene for promising miRNA hairpin structures in silico. Out of the 27 hairpin structures we identified, one stable RNA fold with a promising sequence motive was selected for experimental verification. The exogenous validation of the hairpin sequence was performed by transfection of HEK293T cells and the mature miRNA sequences could be verified by quantitative polymerase chain reaction. The endogenous expression of the mature miRNA provisionally named CDH1‐i2‐miR‐1 could be confirmed in two normal (HEK293T, HUVEK) and five cancer cell lines (MCF7, MDA‐MB‐231, SW480, HT‐29, A549). The functional characterization by the 3‐(4,5‐dimethylthiazol‐2‐yl)−2,5‐diphenyltetrazolium bromide assay showed a suppression of HEK293T cell proliferation. A flow cytometry‐based approach showed the ability of CDH1‐i2‐miR‐1 to arrest transfected cells on a G2/M state while annexin staining exemplified an apoptotic effect. BAX and PTEN expression levels were affected following the overexpression with the new miRNA. The in vivo expression level was assessed in 35 breast tumor tissues and their paired nonmalignant marginal part. A fourfold downregulation in the tumor specimens compared to their marginal controls could be observed. It can be concluded that the sequence of the hub gene CDH1 harbors at least one miRNA but eventually even more relevant for the pathophysiology of breast cancer.
The question of dissection in medical training: Not just “if,” but “when”? A student perspective

While debate about the use of—and alternatives to—human cadaveric dissection in medical training is robust, little attention has been paid to questions about timing. This study explores the perspectives of medical students and recent graduates with regard to two key questions: when in the degree program do students prefer dissection opportunities and what are the students getting out of participating in dissection? Self‐report survey data from students in preclinical years (n = 105), clinical years (n = 57), and graduates (n = 13) were analyzed. Most (89%) preferred dissection during the preclinical years, with no effect by training year (χ2 = 1.98, p = 0.16), previous anatomy (χ2 = 3.64, p = 0.31), or dissection (χ2 = 3.84, p = 0.26) experience. Three key findings emerged. First, the majority of students prefer to dissect in the preclinical years because they view dissection as important for developing foundation knowledge and delivering an opportunity for consolidation prior to transitioning to primarily clinical studies. In addition, students recognize that it is a time‐consuming activity requiring specialized facilities. Second, three main understandings of the purpose of dissection were reported: depth of learning, learning experience, and real‐world equivalence. Third, these student perspectives of the purpose of dissection are associated with timing preferences for dissection opportunities. The results identify the preclinical phase as the optimal time to strategically integrate dissection into medical training in order to maximize the benefits of this unique learning opportunity for students and minimize its impact upon curricular time.
Evaluation of Moddus® As a new chemical ripener for the South African sugar industry: preliminary findings.

Information from Brazil and Australia indicates that trinexapac-ethyl (Moddus ® ) is an excellent new sugarcane ripener. However, there is no information on the response of South African varieties to this chemical. The objective of this investigation was to establish the ripening potential of this chemical in local varieties and to compare responses with the current industry standards, Ethephon ® and Fusilade Forte ® . Evaluation was conducted in drip irrigated plant crops of N27 and N32 at Heatonville and Pongola respectively. Each trial was laid out in a complete randomised replicated design. Ripener treatments comprised (a) untreated control, (b) Ethephon ® applied 84 days before harvest (DBH), (c) Fusilade Forte ® applied 43 DBH, (d) Moddus ® applied at two rates 70 DBH, (e) Ethephon ® and Fusilade Forte ® applied as a combination treatment, and (f) Moddus ® (at two rates) and Fusilade Forte ® applied as combination treatments. At Pongola the various treatments improved estimated recoverable crystal (ERC) yields in N32 by between 1.0-4.3 t/ha compared with the control. Best results were achieved in the combination treatments. However, the two Moddus ® -Fusilade Forte ® combination treatments outperformed the standard Ethephon ® Fusilade Forte ® combination treatment by 1.0 t ERC/ha. At Heatonville ripener responses in N27 were smaller with improvements ranging between 0.5-1.0 t ERC/ha and without clear treatment differences. These preliminary results indicate that Moddus ® is an effective ripener and that a Moddus ® -Fusilade Forte ® combination treatment could increase ERC yields considerably more than current industry standards. Results will be verified in the first ratoon crops at both locations.
Timing of high dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1,384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
Impaired emotional intelligence is related to symptoms severity and suicidal attempts in depression

Objective: Few studies demonstrated the impairment of perceived emotional intelligence ‘EI’ among depressed patients. This study aimed to assess the perceived EI in a group of depressed patients, and its association with different clinical characteristics. Methods: Forty-five patients diagnosed with depression were assessed by the Hamilton Depression Rating Scale and compared to 45 controls that were assessed by the Arabic version of General Health Questionnaire to exclude Psychiatric disorders. The Arabic version of Trait Meta-Mood Scale (TMMS) is used to evaluate EI in both groups. Results: Patients with depression showed significantly lower EI scores in the three parts of TMMS (repair, clarity and attention) compared to the controls (p < .001). Patients showed significant difference in clarity subscale (p = .005) and attention regarding severity of depression (p < .001). Clarity of feelings was significantly higher in patients who suffered more than two episodes (p = .012). Depressive patients with suicidal attempts showed significantly lower scores of repair (p = .044) and attention (p = .016) subscales. There were no significant differences of TMMS subscales between patients with and without suicidal ideation, sleep disturbance and somatic symptoms. Conclusions: The current study demonstrates impaired perceived EI among patients with depression that is correlated with symptom severity and suicidal attempts.
Conditioning Intensity and Peri-Transplant Flow Cytometric MRD Dynamics in Adult AML.

In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established, independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in remission after myeloablative conditioning (MAC; n=515) or non-MAC (n=295) who underwent multiparameter flow cytometry-based MRD testing before and 20-40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85/104 [81.7%]) than non-MAC (33/57 [57.9%]) regimen (P=0.002). Although non-MAC regimens were less likely to clear MRD, if they did the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and "MRD conversion" for relapse (P=0.020), RFS (P=0.002), and OS (P=0.001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared to the isolated use of pre-HCT MRD status and post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments.
The Relationship Between Online Education Pre-school Teachers’ Personality Traits and Job Satisfaction During the COVID-19: The Mediation of Emotional Labour

Online education is an important way to teach students in COVID-19. Online education pre-school teachers as high emotional workers, coupled with the influence of COVID-19, their different emotional labour strategies will have different effects on job satisfaction. Our study investigated the relationship between personality traits, emotional labour and job satisfaction during the COVID-19. A questionnaire survey was administered to 450 pre-school teachers that they worked online at home in China using the Personality Trait Inventory, Emotional Labour Scale and Job Satisfaction Inventory. The results showed that the COVID-19 significantly impacted pre-school teachers' personality traits and emotional labour. First, the Big Five Personalities were significant influences on the emotional labour of pre-school teachers, with openness and agreeableness being strong predictors of surface acting, agreeableness, conscientiousness, openness, and extraversion being effective predictors of deep acting, and agreeableness, conscientiousness, and openness being effective predictors of natural expression. Among them, the most common type of emotional labour for pre-school teachers was deep acting. Secondly, the greatest influence on job satisfaction was openness and agreeableness in the Big Five Personality dimensions. Their effect sizes on job satisfaction were 0.246 and 0.223, respectively. Nervousness was not significantly related to job satisfaction of pre-school teachers. Finally, the Mediation of deep acting and natural expression were more significant between different personality dimensions and job satisfaction of pre-school teachers.
PDBspheres: a method for finding 3D similarities in local regions in proteins

Abstract We present a structure-based method for finding and evaluating structural similarities in protein regions relevant to ligand binding. PDBspheres comprises an exhaustive library of protein structure regions (‘spheres’) adjacent to complexed ligands derived from the Protein Data Bank (PDB), along with methods to find and evaluate structural matches between a protein of interest and spheres in the library. PDBspheres uses the LGA (Local–Global Alignment) structure alignment algorithm as the main engine for detecting structural similarities between the protein of interest and template spheres from the library, which currently contains >2 million spheres. To assess confidence in structural matches, an all-atom-based similarity metric takes side chain placement into account. Here, we describe the PDBspheres method, demonstrate its ability to detect and characterize binding sites in protein structures, show how PDBspheres—a strictly structure-based method—performs on a curated dataset of 2528 ligand-bound and ligand-free crystal structures, and use PDBspheres to cluster pockets and assess structural similarities among protein binding sites of 4876 structures in the ‘refined set’ of the PDBbind 2019 dataset.
Distinct responses to rare codons in select Drosophila tissues

Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index, to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. We further demonstrate a role for rare codons in restricting protein expression of an evolutionarily young gene, RpL10Aa, to the Drosophila testis. Rare codon-mediated restriction of this testis-specific protein is critical for female fertility. Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology.
The neural dynamics associated with computational complexity

Many everyday tasks require people to solve computationally complex problems. However, little is known about the effects of computational hardness on the neural processes associated with solving such problems. Here, we draw on computational complexity theory to address this issue. We performed an experiment in which participants solved several instances of the 0-1 knapsack problem, a combinatorial optimization problem, while undergoing ultra-high field (7T) functional magnetic resonance imaging (fMRI). Instances varied in two task-independent measures of intrinsic computational hardness: complexity and proof hardness. We characterise a network of brain regions whose activation was correlated with both measures but in distinct ways, including the anterior insula, dorsal anterior cingulate cortex and the intra-parietal sulcus/angular gyrus. Activation and connectivity changed dynamically as a function of complexity and proof hardness, in line with theoretical computational requirements. Overall, our results suggest that computational complexity theory provides a suitable framework to study the effects of computational hardness on the neural processes associated with solving complex cognitive tasks.
scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons of PirtEGFPf mice in neuropathic pain condition

Functionally distinct subtypes/clusters of dorsal root ganglion (DRG) neurons, which differ in soma size and neurochemical properties, may play different roles in nerve regeneration and pain. However, details about transcriptomic changes in different neuronal subtypes under maladaptive neuropathic pain conditions remain unclear. Chronic constriction injury (CCI) of the sciatic nerve represents a well-established model of neuropathic pain that mimics the etiology of clinical conditions. Therefore, we conducted single-cell RNA-sequencing (scRNA-seq) to characterize subtype-specific perturbations of transcriptomes in lumbar DRG neurons 7 days after sciatic CCI. By using Pirt-EGFPf mice that selectively express enhanced green fluorescent protein in DRG neurons, we established a highly efficient purification process to enrich neurons for scRNA-seq. We observed a loss of marker genes in injured neurons of 12 standard neuronal clusters, and the emergence of four prominent CCI-induced clusters at this peak-maintenance phase of neuropathic pain. Importantly, a portion of injured neurons from a subset of the 12 standard clusters (NP1, PEP5, NF1, and NF2) were spared from injury-induced identity loss, suggesting subtype-specific transcriptomic changes in injured neurons. Moreover, uninjured neurons, which are necessary for mediating the evoked pain, also demonstrated subtype-specific transcriptomic perturbations in these clusters, but not others. Notably, male and female mice showed differential transcriptomic changes in multiple neuronal clusters after CCI, suggesting transcriptomic sexual dimorphism in primary sensory neurons after nerve injury. Collectively, these findings may contribute to the identification of new target genes and development of DRG neuron subtype-specific therapies for optimizing neuropathic pain treatment and nerve regeneration.
Analytical time-dependent distributions for gene expression models with complex promoter switching mechanisms

Classical gene expression models assume exponential switching time distributions between the active and inactive promoter states. However, recent experiments have shown that many genes in mammalian cells may produce non-exponential switching time distributions, implying the existence of multiple promoter states and molecular memory in the promoter switching dynamics. Here we analytically solve a gene expression model with random bursting and complex promoter switching, and derive the time-dependent distributions of the mRNA and protein copy numbers, generalizing the steady-state solution obtained in [SIAM J. Appl. Math. 72, 789-818 (2012)] and [SIAM J. Appl. Math. 79, 1007-1029 (2019)]. Using multiscale simplification techniques, we find that molecular memory has no influence on the time-dependent distribution when promoter switching is very fast or very slow, while it significantly affects the distribution when promoter switching is neither too fast nor too slow. By analyzing the dynamical phase diagram of the system, we also find that molecular memory in the inactive gene state weakens transient and stationary bimodality of the copy number distribution, while molecular memory in the active gene state enhances such bimodality.
Effects of recombination on the evolvability, genetic diversity and mutational robustness of neutrally evolving populations

Many effects attributed to recombination have been invoked to explain the advantage of sex. The most prominent arguments focus on either evolvability, genetic diversity, or mutational robustness to justify why the benefit of recombination overcomes its costs, with partially contradicting results. As a consequence, understanding which aspects of recombination are most important in a given situation remains an open problem for theoretical and experimental research. In this study, we focus on finite populations evolving on neutral networks, which already display remarkably complex behavior. We aim to provide a comprehensive overview of the effects of recombination by jointly considering different measures of evolvability, genetic diversity, and mutational robustness over a broad parameter range, such that many evolutionary regimes are covered. We find that several of these measures vary non-monotonically with the rates of mutation and recombination. Moreover, the presence of lethal genotypes that introduce inhomogeneities in the network of viable states qualitatively alters the effects of recombination. We conclude that conflicting trends induced by recombination can be explained by an emerging trade-off between evolvability and genetic diversity on the one hand, and mutational robustness and fitness on the other. Finally, we discuss how different implementations of the recombination scheme in theoretical models can affect the observed dependence on recombination rate through a coupling between recombination and genetic drift.
A blunted GPR183/oxysterol axis during dysglycemia results in delayed recruitment of macrophages to the lung during M. tuberculosis infection

We previously reported that the oxidised cholesterol-sensing receptor GPR183 is significantly downregulated in blood from tuberculosis (TB) patients with diabetes compared to TB patients without co-morbidities and that lower GPR183 expression in blood is associated with more severe pulmonary TB on chest-x-ray consistent with observations in dysglycemic mice. To further elucidate the role of this receptor and its endogenous high affinity agonist 7α,25-di-hydroxycholesterol (7α,25-OHC) in the lung, we studied high fat diet (HFD)-induced dysglycemic mice infected with M.tuberculosis. We found that the 7α,25-OHC-producing enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) were highly upregulated upon M. tuberculosis infection in the lungs of normoglycemic mice, and this was associated with increased expression of GPR183 indicative of effective recruitment of GPR183-expressing immune cells to the site of infection. We demonstrated that CYP7B1 was predominantly expressed by macrophages in the centre of TB granulomas. Expression of CYP7B1 was significantly blunted in lungs from HFD-fed dysglycemic animals and this coincided with delayed recruitment of macrophages to the lung during early infection and more severe lung pathology. GPR183 deficient mice similarly had reduced macrophage recruitment during early infection demonstrating a requirement of the GPR183/oxysterol axis for macrophage infiltration into the lung in TB. Together our data demonstrate that oxidised cholesterols and GPR183 play an important role in positioning macrophages to the site of M. tuberculosis infection and that this is impaired by HFD-induced dysglycemia, adding a mechanistic explanation to the poorer TB outcomes in patients with diabetes.