Miracle-dz/UniFAR-FTUs huggingface dataset:
Cross-sectional analysis of pharmaceutical payments to Japanese board-certified gastroenterologists between 2016 and 2019

Objectives Limited evidence is available regarding the financial relationships between gastroenterologists and pharmaceutical companies in Japan. This study analysed the magnitude, prevalence and trends of personal payments made by major pharmaceutical companies to board-certified gastroenterologists in Japan in recent years. Design Cross-sectional analysis Setting and participants Using payment data publicly disclosed by 92 major pharmaceutical companies, this study examined the non-research payments made to all board-certified gastroenterologists by the Japanese Society of Gastroenterology. Primary and secondary outcome measures The primary outcomes were payment amounts, the prevalence of gastroenterologists receiving payments, yearly trends in per-gastroenterologist payment values and the number of gastroenterologists with payments. Additionally, we evaluated the differences in payments among influential gastroenterologists, including clinical practice guideline authors, society board member gastroenterologists and other general gastroenterologists. Results Approximately 52.8% of all board-certified gastroenterologists received a total of US$89 151 253, entailing 134 249 payment contracts as the reimbursement for lecturing, consulting and writing, from 84 pharmaceutical companies between 2016 and 2019. The average and median payments per gastroenterologist were US$7670 (SD: US$26 842) and US$1533 (IQR: US$582–US$4781), respectively. The payment value per gastroenterologist did not significantly change during the study period, while the number of gastroenterologists with payments decreased by −1.01% (95% CI: −1.61% to −0.40%, p<0.001) annually. Board member gastroenterologists (median: US$132 777) and the guideline authoring gastroenterologists (median: US$106 069) received 29.9 times and 17.3 times higher payments, respectively, than general gastroenterologists (median: US$284). Conclusion Most gastroenterologists received personal payments from pharmaceutical companies, but only very few influential gastroenterologists with authority accepted substantial amounts in Japan. There should be transparent and rigorous management strategies for financial conflicts of interest among gastroenterologists working in influential positions.
Fluid mechanics calculations in physics of droplets – IV: Head-on and off-center numerical collisions of unequal-size drops:

In this study, the finite volume method is employed to simulate the coalescence collision between water drops immersed in a continuous phase (n-heptane). For that purpose, it is chosen a range of values for the velocity of collisions for the finite volume calculations may yield different possible outcomes of the collision process. It can be seen for head-on collisions that when the velocity of collision is 0.2 m/s and 3.5 m/s, the little drop induces the formation of a hole in the bigger drop, until the surface tension forces to restore the circular form of the resulting drop. For a velocity of collision of 16.0 m/s, the little drop deforms the bigger one, and the system is converted into a thin ligament with the evolution of the dynamics. In this case, a little mass of n-heptane is trapped between the two drops, but at the end of the dynamics it drains to the continuous phase. For off-center collisions, two different values for the velocity of collisions were chosen, and the drops exhibit a lot of waves .
Assessment for learning in Norway and Portugal: the case of primary school mathematics teaching

In this study, we aim to understand the forces driving assessment for learning (AfL) in primary school teaching. By applying a case study design, including the two cases of Norway and Portugal and using mathematics teaching as an example, available policy documents and research reports are analysed to identify the differences and similarities that might explain the assessment practices previously observed in the two countries. Many similarities are found at the school and national levels. In particular, AfL is introduced as a national policy in both countries. Still, AfL practices are not common in primary mathematics classrooms in either country, although this is true for different reasons in each country. It is suggested that the assessment culture caused by national policies, such as curriculum reforms, national professional development projects and teacher autonomy, explains the similarities in the observed outcomes.
Impedance spectroscopy applied to the fast wounding dynamics of an electrical wound-healing assay in mammalian cells

Electrical wound-healing assays are often used as a means to study in vitro cell migration and proliferation. In such analysis, a cell monolayer that sits on a small electrode is electrically wounded and its spectral impedance is then continuously measured in order to monitor the healing process. The relatively slow dynamics of the cell healing have been extensively studied, while those of the much faster wounding phase have not yet been investigated. An analysis of the electrical properties of a particular cell type during this phase could give extra information about the changes in the cell membrane due to the application of the wounding current, and could also be useful to optimize the wounding regime for different cell types. The main issue when trying to register information about these dynamics is that the traditional measurement scheme employed in typical wound-healing assays doesn’t allow the simultaneous application of the wounding signal and measurement of the system’s impedance. In this paper, we overcome this limitation by implementing a measurement strategy consisting of cycles of fast alternating low- and high-voltage signals applied on electrodes covered with mammalian cells. This approach is capable of registering the fast impedance changes during the transient regime corresponding to the cell wounding process. Furthermore, these quasi-simultaneous high- and low-voltage measurements can be compared in order to obtain an empirical correlation between both quantities.
Colorectal cancer as a model for biological evolution

Complexity in cancer research has led to the creation of powerful analytical tools for helping experimental in vivo and in vitro methods. These tools range from systems of differential equations resolved in computer simulations, to lattice models and agent-based models (ABMs). These analytical methods are focused on studying cell behavior and dynamic cell populations. Among these, those that are increasingly used are ABMs because they can incorporate multi-scale features ranging from the individual up to the population level, mixing rules based on mathematical and conceptual parameters, and combining statistical/population assumptions with individual heterogeneity. In this work, we present an ABM that simulates tumor progression in a colonic crypt, with the aim of providing an experimental in silico environment for testing results achieved in traditional lab research, and developing alternative scenarios of tumor development. As the first part of an ongoing project, the long-term goal is to reproduce and study, the general evolutionary mechanisms of a biological system.
Proliferative response of ERα-positive breast cancer cells to 10 μM enterolactone, and the associated alteration in the transcriptomic landscape

Enterolactone (EL) is a product of gut-microbial metabolism of dietary plant lignans. Studies linking EL with breast cancer risk have bolstered investigations into its effects on the mammary epithelial cells, and the mechanisms thereof. While it binds to the estrogen receptor α; ERα, its effect on the proliferation of mammary tumor cell lines is reportedly ambivalent; depending on its concentration. The genomic correlates of EL actions also remain unexplored. Here we have elaborately studied the effect of EL on proliferation of ERα-positive, and ERα-negative cell lines. 10 µM EL significantly enhanced the growth of the ERα-positive MCF-7 or T47D breast cancer cells, but not the ERα-negative MDA-MB-231 or MDA-MB-453 cells. In MCF-7 cells, it significantly increased the expression of TFF1 mRNA, an estrogen-induced transcript. The binding of ERα to the estrogen response element within the TFF1 locus further demonstrates the pro-estrogenic effect of 10 µM EL. We further explored the genome-wide transcriptomic effect of 10 µM EL. Analysis of RNA-seq data obtained from control- or 10 µM EL treated-MCF-7 cells revealed modulation of expression of diverse sets of functionally related genes, which reflected cell cycle progression, rather than cell cycle arrest or apoptosis. The manner in which 10 µM EL regulated the hallmark G2/M checkpoint, and estrogen-response-late genes correlated with proliferation inducing, and estrogen-like effects of EL on MCF-7 cells.
Light modulates task-dependent thalamo-cortical connectivity during an auditory attentional task

The brain activity of 19 healthy young participants was recorded at 7 T MRI while performing an auditory oddball task under different light conditions. Only blue-enriched light strengthens subcortico-cortical connectivity (thalamus-to-IPS connection). Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. Here we record the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they complete an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We test if light modulates the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We find that only the blue-enriched light strengthens the connection from the posterior thalamus to the IPS. To the best of our knowledge, our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.
Modeling Synaptic Integration of Bursty and β Oscillatory Inputs in Ventromedial Motor Thalamic Neurons in Normal and Parkinsonian States

Abstract The ventromedial motor thalamus (VM) is implicated in multiple motor functions and occupies a central position in the cortico-basal ganglia-thalamocortical loop. It integrates glutamatergic inputs from motor cortex (MC) and motor-related subcortical areas, and it is a major recipient of inhibition from basal ganglia. Previous in vitro experiments performed in mice showed that dopamine depletion enhances the excitability of thalamocortical (TC) neurons in VM due to reduced M-type potassium currents. To understand how these excitability changes impact synaptic integration in vivo, we constructed biophysically detailed mouse VM TC model neurons fit to normal and dopamine-depleted conditions, using the NEURON simulator. These models allowed us to assess the influence of excitability changes with dopamine depletion on the integration of synaptic inputs expected in vivo. We found that VM neuron models in the dopamine-depleted state showed increased firing rates with the same synaptic inputs. Synchronous bursting in inhibitory input from the substantia nigra pars reticulata (SNR), as observed in parkinsonian conditions, evoked a postinhibitory firing rate increase with a longer duration in dopamine-depleted than control conditions, due to different M-type potassium channel densities. With β oscillations in the inhibitory inputs from SNR and the excitatory inputs from cortex, we observed spike-phase locking in the activity of the models in normal and dopamine-depleted states, which relayed and amplified the oscillations of the inputs, suggesting that the increased β oscillations observed in VM of parkinsonian animals are predominantly a consequence of changes in the presynaptic activity rather than changes in intrinsic properties.
Whole-Brain Deactivations Precede Uninduced Mind-Blanking Reports

Mind-blanking (MB) is termed as the inability to report our immediate-past mental content. In contrast to mental states with reportable content, such as mind-wandering or sensory perceptions, the neural correlates of MB started getting elucidated only recently. A notable particularity that pertains to MB studies is the way MB is instructed for reporting, like by deliberately asking participants to “empty their minds. ” Such instructions were shown to induce fMRI activations in frontal brain regions, typically associated with metacognition and self-evaluative processes, suggesting that MB may be a result of intentional mental content suppression. Here, we aim at examining this hypothesis by determining the neural correlates of MB without induction. Using fMRI combined with experience-sampling in 31 participants (22 female), univariate analysis of MB reports revealed deactivations in occipital, frontal, parietal, and thalamic areas, but no activations in prefrontal regions. These findings were confirmed using Bayesian region-of-interest analysis on areas previously shown to be implicated in induced MB, where we report evidence for frontal deactivations during MB reports compared with other mental states. Contrast analysis between reports of MB and content-oriented mental states also revealed deactivations in the left angular gyrus. We propose that these effects characterize a neuronal profile of MB, where key thalamocortical nodes are unable to communicate and formulate reportable content. Collectively, we show that study instructions for MB lead to differential neural activation. These results provide mechanistic insights linked to the phenomenology of MB and point to the possibility of MB being expressed in different forms. SIGNIFICANCE STATEMENT This study explores how brain activity changes when individuals report unidentifiable thoughts, a phenomenon known as mind-blanking (MB). It aims to detect changes in brain activations and deactivations when MB is reported spontaneously, as opposed to the neural responses that have been previously reported when MB is induced. By means of brain imaging and experience-sampling, the study points to reduced brain activity in a wide number of regions, including those mesio-frontally which were previously detected as activated during induced MB. These results enhance our understanding of the complexity of spontaneous thinking and contribute to broader discussions on consciousness and reportable experience.
Gardnerella vaginolysin potentiates glycan molecular mimicry by Neisseria gonorrhoeae

Bacterial vaginosis (BV) is a condition of the vaginal microbiome in which there are lower levels of “healthy” Lactobacillus species and an outgrowth of diverse anaerobic bacteria. BV is associated with increased risk of infection by the bacterium Neisseria gonorrhoeae - the causative agent of gonorrhea. Here we test if one known facet of BV - the presence of bacterial cytolysins – leads to the mobilization of specific intracellular contents that aid in gonococcal virulence. We cloned and expressed recombinant vaginolysin (VLY), a cytolysin produced by the BV-associated bacterium Gardnerella, verifying that it liberates the contents of red blood cells and cervical epithelial (HeLa) cells while vector control preparations made in parallel did not. We tested if VLY mediates a well-known virulence mechanism of gonococcus – the molecular mimicry of host glycans. To evade host immunity, N. gonorrhoeae caps its surface lipooligosaccharide (LOS) with α2-3-linked sialic acid. To do this, gonococci must scavenge an intermediate metabolite made and used inside host cells. Flow-cytometry based lectin-binding assays showed that, compared to controls, gonococci exposed to vaginolysin-liberated contents of HeLa cells displayed greater sialic acid capping of their LOS. This higher level of bacterial sialylation was accompanied by increased binding of the complement regulatory protein Factor H, and greater resistance to complement attack. Together these results suggest that cytolytic activities present during BV may enhance the ability of N. gonorrhoeae to capture intracellular metabolites and evade host immunity via glycan molecular mimicry.
Activation loop plasticity and active site coupling in the MAP kinase, ERK2

Changes in the dynamics of the protein kinase, ERK2, have been shown to accompany its activation by dual phosphorylation. However, our knowledge about the conformational changes represented by these motions is incomplete. Previous NMR relaxation dispersion studies showed that active, dual-phosphorylated ERK2 undergoes global exchange between at least two energetically similar conformations. These findings, combined with measurements by hydrogen exchange mass spectrometry (HX-MS), suggested that the global conformational exchange involves motions of the activation loop (A-loop) that are coupled to regions surrounding the kinase active site. In order to better understand the contribution of dynamics to the activation of ERK2, we applied long conventional molecular dynamics (MD) simulations starting from crystal structures of active, phosphorylated (2P), and inactive, unphosphorylated (0P) ERK2. Individual trajectories were run for (5 to 25) µs and totaled 727 µs. The results showed that the A-loop is unexpectedly flexible in both 2P- and 0P-ERK2, and able to adopt multiple long-lived (>5 µs) conformational states. Simulations starting from the X-ray structure of 2P-ERK2 (2ERK) revealed A-loop states corresponding to restrained dynamics within the N-lobe, including regions surrounding catalytic residues. One A-loop conformer forms lasting interactions with the C-terminal L16 segment and shows reduced RMSF and greater compaction in the active site. By contrast, simulations starting from the most common X-ray conformation of 0P-ERK2 (5UMO) reveal frequent excursions of A-loop residues away from a C-lobe docking site pocket and towards a new state that shows greater dynamics in the N-lobe and disorganization around the active site. Thus, the A-loop in ERK2 appears to switch between distinct conformational states that reflect allosteric coupling with the active site, likely occurring via the L16 segment. Analyses of crystal packing interactions across many structural datasets suggest that the A-loop observed in X-ray structures of ERK2 may be driven by lattice contacts and less representative of the solution structure. The novel conformational states identified by MD expand our understanding of ERK2 regulation, by linking the activated state of the kinase to reduced dynamics and greater compaction surrounding the catalytic site.
Convex Minimization with Integer Minima in Õ(n4) Time

Given a convex function $f$ on $\mathbb{R}^n$ with an integer minimizer, we show how to find an exact minimizer of $f$ using $O(n^2 \log n)$ calls to a separation oracle and $O(n^4 \log n)$ time. The previous best polynomial time algorithm for this problem given in [Jiang, SODA 2021, JACM 2022] achieves $O(n^2\log\log n/\log n)$ oracle complexity. However, the overall runtime of Jiang's algorithm is at least $\widetilde{\Omega}(n^8)$, due to expensive sub-routines such as the Lenstra-Lenstra-Lov\'asz (LLL) algorithm [Lenstra, Lenstra, Lov\'asz, Math. Ann. 1982] and random walk based cutting plane method [Bertsimas, Vempala, JACM 2004]. Our significant speedup is obtained by a nontrivial combination of a faster version of the LLL algorithm due to [Neumaier, Stehl\'e, ISSAC 2016] that gives similar guarantees, the volumetric center cutting plane method (CPM) by [Vaidya, FOCS 1989] and its fast implementation given in [Jiang, Lee, Song, Wong, STOC 2020]. For the special case of submodular function minimization (SFM), our result implies a strongly polynomial time algorithm for this problem using $O(n^3 \log n)$ calls to an evaluation oracle and $O(n^4 \log n)$ additional arithmetic operations. Both the oracle complexity and the number of arithmetic operations of our more general algorithm are better than the previous best-known runtime algorithms for this specific problem given in [Lee, Sidford, Wong, FOCS 2015] and [Dadush, V\'egh, Zambelli, SODA 2018, MOR 2021].
Phage combination alleviates bacterial leaf blight of rice (Oryza sativa L.)

Rice bacterial leaf blight (BLB) is the most destructive bacterial diseases caused by Xanthomonas oryzae pv. oryzae (Xoo). Phages have been proposed as a green and efficient strategy to kill bacterial pathogens in crops, however, the mechanism of action of phages in the control of phyllosphere bacterial diseases remain unclear. Here, the glasshouse pot experiment results showed that phage combination could reduce the disease index by up to 64.3%. High-throughput sequencing technology was used to analyze the characteristics of phyllosphere microbiome changes and the results showed that phage combinations restored the impact of pathogen invasion on phyllosphere communities to a certain extent, and increased the diversity of bacterial communities. In addition, the phage combination reduced the relative abundance of epiphytic and endophytic Xoo by 58.9% and 33.9%, respectively. In particular, Sphingomonas and Stenotrophomonas were more abundant. According to structural equation modeling, phage combination directly and indirectly affected the disease index by affecting pathogen Xoo biomass and phage resistance. In summary, phage combination could better decrease the disease index. These findings provide new insights into phage biological control of phyllosphere bacterial diseases, theoretical data support, and new ideas for agricultural green prevention and control of phyllosphere diseases.
Bacterial community responses to planktonic and terrestrial substrates in coastal northern Baltic Sea

Bacteria are major consumers of dissolved organic matter (DOM) in aquatic systems. In coastal zones, bacteria are exposed to a variety of DOM types originating from land and open sea. Climate change is expected to cause increased inflows of freshwater to the northern coastal zones, which may lead either to eutrophication or to increased inputs of refractory terrestrial compounds. The compositional and functional response of bacterial communities to such changes is not well understood. We performed a 2-day microcosm experiment in two bays in the coastal northern Baltic Sea, where we added plankton extract to simulate eutrophication and soil extract to simulate increased inputs of refractory terrestrial compounds. Our results showed that the bacterial communities responded differently to the two types of food substrates but responded in a similar compositional and functional way in both bays. Plankton extract addition induced a change of bacterial community composition, while no significant changes occurred in soil extract treatments. Gammaproteobacteria were promoted by plankton extract, while Alphaproteobacteria dominated in soil extract addition and in the non-amended controls. Carbohydrate metabolism genes, such as aminoglycan and chitin degradation, were enriched by plankton extract, but not soil extract. In conclusion, the coastal bacterial communities rapidly responded to highly bioavailable substrates, while terrestrial matter had minor influence and degraded slowly. Thus, in the northern Baltic Sea, if climate change leads to eutrophication, large changes of the bacterial community composition and function can be expected, while if climate change leads to increased inflow of refractory terrestrial organic matter the bacterial communities will not show fast compositional and functional changes. Degradation of terrestrial organic matter may instead occur over longer periods of time, e.g. years. These findings help to better understand the ability of bacterial communities to utilize different carbon sources and their role in the ecosystem.