Miracle-dz/UniFAR-FTUs huggingface dataset:
Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury

Alveolar inflammation is a hallmark of acute lung injury (ALI), and its clinical correlate is acute respiratory distress syndrome—and it is as a result of interactions between alveolar type II cells (ATII) and alveolar macrophages (AM). In the setting of acute injury, the microenvironment of the intra‐alveolar space is determined in part by metabolites and cytokines and is known to shape the AM phenotype. In response to ALI, increased glycolysis is observed in AT II cells, mediated by the transcription factor hypoxia‐inducible factor (HIF) 1α, which has been shown to decrease inflammation. We hypothesized that in acute lung injury, lactate, the end product of glycolysis, produced by ATII cells shifts AMs toward an anti‐inflammatory phenotype, thus mitigating ALI. We found that local intratracheal delivery of lactate improved ALI in two different mouse models. Lactate shifted cytokine expression of murine AMs toward increased IL‐10, while decreasing IL‐1 and IL‐6 expression. Mice with ATII‐specific deletion of Hif1a and mice treated with an inhibitor of lactate dehydrogenase displayed exacerbated ALI and increased inflammation with decreased levels of lactate in the bronchoalveolar lavage fluid; however, all those parameters improved with intratracheal lactate. When exposed to LPS (to recapitulate an inflammatory stimulus as it occurs in ALI), human primary AMs co‐cultured with alveolar epithelial cells had reduced inflammatory responses. Taken together, these studies reveal an innate protective pathway, in which lactate produced by ATII cells shifts AMs toward an anti‐inflammatory phenotype and dampens excessive inflammation in ALI.
Long‐term recruitment of peripheral immune cells to brain scars after a neonatal insult

Although brain scars in adults have been extensively studied, there is less data available regarding scar formation during the neonatal period, and the involvement of peripheral immune cells in this process remains unexplored in neonates. Using a murine model of neonatal hypoxic–ischemic encephalopathy (HIE) and confocal microscopy, we characterized the scarring process and examined the recruitment of peripheral immune cells to cortical and hippocampal scars for up to 1 year post‐insult. Regional differences in scar formation were observed, including the presence of reticular fibrotic networks in the cortex and perivascular fibrosis in the hippocampus. We identified chemokines with chronically elevated levels in both regions and demonstrated, through a parabiosis‐based strategy, the recruitment of lymphocytes, neutrophils, and monocyte‐derived macrophages to the scars several weeks after the neonatal insult. After 1 year, however, neutrophils and lymphocytes were absent from the scars. Our data indicate that peripheral immune cells are transient components of HIE‐induced brain scars, opening up new possibilities for late therapeutic interventions.
A sodium/potassium switch for G4-prone G/C-rich sequences

Abstract Metal ions are essential components for the survival of living organisms. For most species, intracellular and extracellular ionic conditions differ significantly. As G-quadruplexes (G4s) are ion-dependent structures, changes in the [Na+]/[K+] ratio may affect the folding of genomic G4s. More than 11000 putative G4 sequences in the human genome (hg19) contain at least two runs of three continuous cytosines, and these mixed G/C-rich sequences may form a quadruplex or a competing hairpin structure based on G-C base pairing. In this study, we examine how the [Na+]/[K+] ratio influences the structures of G/C-rich sequences. The natural G4 structure with a 9-nt long central loop, CEBwt, was chosen as a model sequence, and the loop bases were gradually replaced by cytosines. The series of CEB mutations revealed that the presence of cytosines in G4 loops does not prevent G4 folding or decrease G4 stability but increases the probability of forming a competing structure, either a hairpin or an intermolecular duplex. Slow conversion to the quadruplex in vitro (in a potassium-rich buffer) and cells was demonstrated by NMR. ‘Shape-shifting’ sequences may respond to [Na+]/[K+] changes with delayed kinetics.
Grouped Multivariate Variational Mode Decomposition With Application to EEG Analysis

Objective: In this paper, a novel extended form of multivariate variational mode decomposition (MVMD) method to multigroup data named as grouped MVMD (GMVMD) is proposed. GMVMD is distinct from MVMD as it extracts common frequencies with strong correlations among regional channels. Methods: Firstly, GMVMD utilizes a new clustering algorithm named as frequencies grouping algorithm to classify the nearest common frequencies among all channels to specified groups. Secondly, a generic variational optimization model which is extended from MVMD is formulated. Thirdly, alternating direction method of multipliers (ADMM) is utilized to obtain optimal solution of GMVMD model. Results: The proposed method introduces an extra parameter to decide the number of clusterings which need to be specified by the user. The effectiveness and superiority of the algorithm are demonstrated on a series of experiments. The utility of GMVMD is verified by grouping real-world electroencephalogram (EEG) data having similar center frequencies successfully. Conclusion: GMVMD outperforms MVMD in mode-alignment, signal reduction error and et al. Significance: GMVMD can obtain more accurate center frequencies and less signal reduction error than MVMD.
Mechanistic basis of ligand efficacy in the calcium‐activated chloride channel TMEM16A

Agonist binding in ligand‐gated ion channels is coupled to structural rearrangements around the binding site, followed by the opening of the channel pore. In this process, agonist efficacy describes the equilibrium between open and closed conformations in a fully ligand‐bound state. Calcium‐activated chloride channels in the TMEM16 family are important sensors of intracellular calcium signals and are targets for pharmacological modulators, yet a mechanistic understanding of agonist efficacy has remained elusive. Using a combination of cryo‐electron microscopy, electrophysiology, and autocorrelation analysis, we now show that agonist efficacy in the ligand‐gated channel TMEM16A is dictated by the conformation of the pore‐lining helix α6 around the Ca2+‐binding site. The closure of the binding site, which involves the formation of a π‐helix below a hinge region in α6, appears to be coupled to the opening of the inner pore gate, thereby governing the channel's open probability and conductance. Our results provide a mechanism for agonist binding and efficacy and a structural basis for the design of potentiators and partial agonists in the TMEM16 family.
The Oblique Seismic Experiment on DSDP Leg 52

Summary. The Oblique Seismic Experiment (OSE) has been proposed to increase the usefulness of the IPOD crustal borehole as a means of investigating layer 2 of oceanic crust. Specific objectives are: to determine the lateral extent of the structure intersected by the borehole, to analyse the role of cracks in the velocity structure of layer 2, to look for anisotropy which may be caused by large cracks with a preferred orientation and, finally, to measure attenuation in oceanic crust. The first successful Oblique Seismic Experiment in oceanic crust was carried out in 1977 March in a hole 400 miles north of Puerto Rico. An adequate study of lateral velocity variations was impossible because the hole was not deep enough, the hole was inadequately logged, and the small scale basement topography was not known. In general both P- and S-wave velocity profiles suggest that the crack density decreases with depth in layer 2. Velocities at the bottom of layer 2 are the same as matrix velocities for basalt, implying that crack density may be negligible at this depth. No convincing evidence for anisotropy in either layer 2 or 3 is found from travel time analysis. The hole was not deep enough to measure attenuation from normal incidence shots and amplitudes were not consistent enough to obtain a measure of attenuation from long range shots. 1 Objectives of the OSE
Brn3b regulates the formation of fear-related midbrain circuits and defensive responses to visual threat

Defensive responses to visually threatening stimuli represent an essential fear-related survival instinct, widely detected across species. The neural circuitry mediating visually triggered defensive responses has been delineated in the midbrain. However, the molecular mechanisms regulating the development and function of these circuits remain unresolved. Here, we show that midbrain-specific deletion of the transcription factor Brn3b causes a loss of neurons projecting to the lateral posterior nucleus of the thalamus. Brn3b deletion also down-regulates the expression of the neuropeptide tachykinin 2 (Tac2). Furthermore, Brn3b mutant mice display impaired defensive freezing responses to visual threat precipitated by social isolation. This behavioral phenotype could be ameliorated by overexpressing Tac2, suggesting that Tac2 acts downstream of Brn3b in regulating defensive responses to threat. Together, our experiments identify specific genetic components critical for the functional organization of midbrain fear-related visual circuits. Similar mechanisms may contribute to the development and function of additional long-range brain circuits underlying fear-associated behavior.
Dynamic Activity Model of Movement Disorders: The Fundamental Role of the Hyperdirect Pathway

Schematic illustration of cortically induced dynamic activity changes of the output nuclei of the basal ganglia (the internal segment of the globus pallidus, GPi and the substantia nigra pars reticulata, SNr) in the healthy and diseased states. The height of the dam along the time course controls the expression of voluntary movements. Its alterations could cause a variety of movement disorders, such as Parkinson's disease and hyperkinetic disorders. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Resistance gene–guided genome mining reveals the roseopurpurins as inhibitors of cyclin-dependent kinases

Significance Resistance gene–guided genome mining presents a solution to a longstanding challenge in natural product drug discovery by allowing the prediction of a natural product’s molecular target directly from the sequence of the gene cluster responsible for its biosynthesis. We apply the approach to reveal roseopurpurin C as a potent inhibitor of Cyclin-dependent kinase 2 (CDK2). This work represents an example of the use of resistance gene–guided genome mining in fungi for the identification of an inhibitor of a target that has been clinically validated for the treatment of multiple cancers.
Piezoionic High Performance Hydrogel Generator and Active Protein Absorber via Microscopic Porosity and Phase Blending

Generating electricity in hydrogel is very important but remains difficult. Hydrogel with electricity generation capability is more capable in bio‐relevant tasks such as tissue engineering, artificial skin, or medical treatment, because electricity is indispensable in regulating physiological activities. Here, a porous and phase blending hydrogel structure for effective piezoionic electricity generation is developed. Dynamic electric field is generated taking advantage of the difference in streaming speeds of sodium and chloride in the material. Microscopic porosity and hydrophilic‐hydrophobic phase blending are the two key factors for prominent piezoionic performance. Voltages as high as 600 mV are first realized in hydrogels in response to medical ultrasound stimulation. The hydrogel structure is also subjective to effective substance exchange and can actively enrich proteins from surroundings under mechanical stimuli. Preliminary applications in neural stimulation, constructing complex spatial‐temporal chemical and electric field distribution patterns, mimetic tactile sensor, sample pretreatment in fast detection, and enzyme immobilization are demonstrated.
The effect of fire on tree–grass coexistence in savannas: a simulation study

The savanna biome has the greatest burned area globally. Whereas the global distribution of most biomes can be predicted successfully from climatic variables, this is not so for savannas. Attempts to dynamically model the distribution of savannas, including a realistically varying tree : grass ratio are fraught with difficulties. In a simulation study using the dynamic vegetation model LPJ-GUESS we investigate the effect of fire on the tree : grass ratios as well as the biome distribution on the African continent. We performed simulations at three spatial scales: locally, at four sites inside Kruger National Park (South Africa); regionally, along a precipitation gradient; and for the African continent. We evaluated the model using results of a fire experiment and found that the model underestimates the effect of fire on tree cover slightly. On a regional scale, high frequencies were able to prevent trees from outcompeting grasses in mesic regions between ~700 and 900 mm mean annual precipitation. Across the African continent, incorporation of fire improved notably the simulated distribution of the savanna biome. Our model results confirm the role of fire in determining savanna distributions, a notion that has been challenged by competing theories of tree–grass coexistence.
The LysR‐type transcription factor LsrB regulates beta‐lactam resistance in Agrobacterium tumefaciens

Agrobacterium tumefaciens is a plant pathogen, broadly known as the causal agent of the crown gall disease. The soil bacterium is naturally resistant to beta‐lactam antibiotics by utilizing the inducible beta‐lactamase AmpC. Our picture on the condition‐dependent regulation of ampC expression is incomplete. A known regulator is AmpR controlling the transcription of ampC in response to unrecycled muropeptides as a signal for cell wall stress. In our study, we uncovered the global transcriptional regulator LsrB as a critical player acting upstream of AmpR. Deletion of lsrB led to severe ampicillin and penicillin sensitivity, which could be restored to wild‐type levels by lsrB complementation. By transcriptome profiling via RNA‐Seq and qRT‐PCR and by electrophoretic mobility shift assays, we show that ampD coding for an anhydroamidase involved in peptidoglycan recycling is under direct negative control by LsrB. Controlling AmpD levels by the LysR‐type regulator in turn impacts the cytoplasmic concentration of cell wall degradation products and thereby the AmpR‐mediated regulation of ampC. Our results substantially expand the existing model of inducible beta‐lactam resistance in A. tumefaciens by establishing LsrB as higher‐level transcriptional regulator.
Discovery of small molecule c‐Maf inhibitors using molecular docking‐based virtual screening, molecular dynamics simulation, and biological evaluation

Multiple myeloma (MM) is a prevalent plasma cell malignancy in the blood system that remains incurable. Given the abnormally high expression of c‐Maf in most MM patients, targeting c‐Maf presents an attractive therapeutic approach for treating MM malignancies. In this study, we employed a combined strategy involving molecular docking‐based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation on existing FDA‐approved drugs. Six compounds were selected for further experimental assay: vemurafenib, sorafenib, sildenafil, fluvastatin, erlotinib, and glimepiride. Among these compounds, sorafenib and glimepiride exhibited significant inhibition of myeloma cell proliferation in the RPMI‐8226 cell line. Moreover, both compounds simultaneously downregulated c‐Maf protein expression to induce G1 phase arrest and apoptosis in myeloma cells. Collectively, sorafenib and glimepiride may be considered promising candidates for developing more potent c‐Maf inhibitors in the future.
Evaluation of the use of a heparin dose‐response test in dogs to determine the optimal heparin dose during intravascular procedures and assessment of the in vitro heparin response in healthy dogs

Abstract Background No guidelines for administering and monitoring anticoagulants intraprocedurally are currently available in dogs, despite the prevalence of procedures necessitating systemic anticoagulation with heparin. Objectives To evaluate an activated clotting time (ACT)‐based heparin dose‐response (HDR) test to predict the individual required heparin dose in dogs during intravascular procedures, and to investigate both the in vitro heparin – ACT and in vitro heparin – factor anti‐Xa activity (anti‐Xa) relationships in dogs. Methods Blood was collected from eight healthy beagles undergoing a cardiac procedure and utilised to establish baseline ACT and for in vitro evaluation. Subsequently, 100 IU/kg heparin was administered intravenously (IV) and ACT was remeasured (HDR test). The required heparin dose for an ACT target response ≥300 s was calculated for each individual and ACT was remeasured after administration of this dose. For in vitro testing, a serial heparin blood dilution (0‐0.5‐1‐2‐4 international unit (IU)/mL) was prepared and ACT and anti‐Xa were determined using whole blood and frozen plasma, respectively. Results The HDR test overestimated the required heparin dose in 3/7 dogs. In vitro, ACT and anti‐Xa increased significantly with increasing blood heparin concentration. Heparin – ACT was nonlinear in 4/8 dogs at heparin concentrations >2 IU/mL, whereas heparin – anti‐Xa remained linear throughout the tested range. Conclusions The HDR test poorly estimated the required heparin dose in dogs. This is most likely attributed to a nonlinear heparin – ACT relationship, as observed in vitro. Anti‐Xa is a promising alternative for ACT; however, unavailability as a point‐of‐care test and lack of in vivo target values restrict its current use.
Age‐related anatomical variation and morphometric studies on the optic tectum in post‐hatch broiler chicken

In this investigation the morphological and morphometrical features of the optic tectum in post‐hatch broiler chicken were studied macroscopically and microscopically. The present study was conducted on 70 day old broiler chicks which were reared up to 42 days. The whole experimental period of study was divided into seven groups (from group I to VII) at weekly interval (days 0, 7, 14, 21, 28, 35 and 42). The optic lobes were paired and spherical to oval eminences located on the ventro‐lateral part of the midbrain in broiler chicken. There was significant increase in length and width of the optic lobes with the advancement of age. Histological analysis of optic tectum shows six basic layers from the external surface to internal one towards the optic ventricle. Different layers of optic tectum were identified as stratum opticum, stratum griseum superficial, stratum griseum central, stratum album central, stratum griseum periventriculare and stratum fibrosum periventriculare with several types of neurons. Among all six layers of the optic tectum the stratum griseum superficial layer showed very high degree of secondry differentiation and evolved into nine sub‐ layers in all age groups of broiler chickens. Three main cell types had been identified that is, small to medium sized stellate shaped neuron, pyramidal neuron and fusiform neuron, beside these multipolar neuron were also evident. The thickness of all layers of optic tectum significantly increases with the advancement of age of the birds. The optic ventricle was lined with a layer of cuboidal ependymal cells.
Predictors of outcome in sciatica patients following an epidural steroid injection: the POiSE prospective observational cohort study protocol

Introduction Sciatica can be very painful and, in most cases, is due to pressure on a spinal nerve root from a disc herniation with associated inflammation. For some patients, the pain persists, and one management option is a spinal epidural steroid injection (ESI). The aim of an ESI is to relieve leg pain, improve function and reduce the need for surgery. ESIs work well in some patients but not in others, but we cannot identify these patient subgroups currently. This study aims to identify factors, including patient characteristics, clinical examination and imaging findings, that help in predicting who does well and who does not after an ESI. The overall objective is to develop a prognostic model to support individualised patient and clinical decision-making regarding ESI. Methods POiSE is a prospective cohort study of 439 patients with sciatica referred by their clinician for an ESI. Participants will receive weekly text messages until 12 weeks following their ESIand then again at 24 weeks following their ESI to collect data on leg pain severity. Questionnaires will be sent to participants at baseline, 6, 12 and 24 weeks after their ESI to collect data on pain, disability, recovery and additional interventions. The prognosis for the cohort will be described. The primary outcome measure for the prognostic model is leg pain at 6 weeks. Prognostic models will also be developed for secondary outcomes of disability and recovery at 6 weeks and additional interventions at 24 weeks following ESI. Statistical analyses will include multivariable linear and logistic regression with mixed effects model. Ethics and dissemination The POiSE study has received ethical approval (South Central Berkshire B Research Ethics Committee 21/SC/0257). Dissemination will be guided by our patient and public engagement group and will include scientific publications, conference presentations and social media.
Exploring strategy differences between humans and monkeys with recurrent neural networks

Animal models are used to understand principles of human biology. Within cognitive neuroscience, non-human primates are considered the premier model for studying decision-making behaviors in which direct manipulation experiments are still possible. Some prominent studies have brought to light major discrepancies between monkey and human cognition, highlighting problems with unverified extrapolation from monkey to human. Here, we use a parallel model system—artificial neural networks (ANNs)—to investigate a well-established discrepancy identified between monkeys and humans with a working memory task, in which monkeys appear to use a recency-based strategy while humans use a target-selective strategy. We find that ANNs trained on the same task exhibit a progression of behavior from random behavior (untrained) to recency-like behavior (partially trained) and finally to selective behavior (further trained), suggesting monkeys and humans may occupy different points in the same overall learning progression. Surprisingly, what appears to be recency-like behavior in the ANN, is in fact an emergent non-recency-based property of the organization of the neural network’s state space during its development through training. We find that explicit encouragement of recency behavior during training has a dual effect, not only causing an accentuated recency-like behavior, but also speeding up the learning process altogether, resulting in an efficient shaping mechanism to achieve the optimal strategy. Our results suggest a new explanation for the discrepency observed between monkeys and humans and reveal that what can appear to be a recency-based strategy in some cases may not be recency at all.