Miracle-dz/UniFAR-FTUs huggingface dataset:
A Patient With Miller Fisher Syndrome With Positive GQ1b and Aquaporin-4 Antibodies: Will There Be an Aquaporin-4 Antibody Associated Disorder?

There have been many advancements in the field of neuromyelitis optica and neuromyelitis optica spectrum disorder since the discovery of aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein antibodies. It is also recognized that the pathological features associated with myelin oligodendrocyte glycoprotein antibodies are beyond the domain of neuromyelitis optica spectrum disorder and there is a separate nomenclature, namely myelin oligodendrocyte glycoprotein antibody associated disease. Currently, there is no aquaporin-4 antibody associated disorder, even though aquaporin-4 antibodies are not as widely present in other disorders. Miller Fisher syndrome (MFS) is a variant of Guillain Barré syndrome, in which there are positive GQ1b antibodies with no evidence of myelitis or optic neuritis. MFS is not considered a component of neuromyelitis optica spectrum disorder. We report on a patient with MFS that was positive for GQ1b and aquaporin-4 antibodies but negative for myelin oligodendrocyte glycoprotein antibodies and is devoid of any features of neuromyelitis optica spectrum disorder. This finding may lead to investigations and reports of other pathologies that are associated with the aquaporin-4 antibody.
Structural basis for the disaggregase activity and regulation of Hsp104

The Hsp104 disaggregase is a two-ring ATPase machine that rescues various forms of non-native proteins including the highly resistant amyloid fibers. The structural-mechanistic underpinnings of how the recovery of toxic protein aggregates is promoted and how this potent unfolding activity is prevented from doing collateral damage to cellular proteins are not well understood. Here, we present structural and biochemical data revealing the organization of Hsp104 from Chaetomium thermophilum at 3.7 Å resolution. We show that the coiled-coil domains encircling the disaggregase constitute a ‘restraint mask’ that sterically controls the mobility and thus the unfolding activity of the ATPase modules. In addition, we identify a mechanical linkage that coordinates the activity of the two ATPase rings and accounts for the high unfolding potential of Hsp104. Based on these findings, we propose a general model for how Hsp104 and related chaperones operate and are kept under control until recruited to appropriate substrates. DOI: http://dx.doi. org/10.7554/eLife.21516. 001
Genetic architecture of plant stress resistance: multi‐trait genome‐wide association mapping

Summary Plants are exposed to combinations of various biotic and abiotic stresses, but stress responses are usually investigated for single stresses only. Here, we investigated the genetic architecture underlying plant responses to 11 single stresses and several of their combinations by phenotyping 350 Arabidopsis thaliana accessions. A set of 214 000 single nucleotide polymorphisms (SNPs) was screened for marker‐trait associations in genome‐wide association (GWA) analyses using tailored multi‐trait mixed models. Stress responses that share phytohormonal signaling pathways also share genetic architecture underlying these responses. After removing the effects of general robustness, for the 30 most significant SNPs, average quantitative trait locus (QTL) effect sizes were larger for dual stresses than for single stresses. Plants appear to deploy broad‐spectrum defensive mechanisms influencing multiple traits in response to combined stresses. Association analyses identified QTLs with contrasting and with similar responses to biotic vs abiotic stresses, and below‐ground vs above‐ground stresses. Our approach allowed for an unprecedented comprehensive genetic analysis of how plants deal with a wide spectrum of stress conditions.
ChiRP: Chinese Restaurant Process Mixtures for Regression and Clustering

These are common tasks in biomedical research. However, regression often involves parametric assumptions (e.g. normality, linearity, constant variance). Similarly, clustering often involves pre-specifying the number of clusters typically unknown to the researcher. Flexible machine learning methods exist for such problems, but they focus on predictive accuracy, making them inadequate for biomedical research applications where inference and interval estimation are of interest.
Hypoxia Inducible Factor-1 (cid:1) –Independent Suppression of Aryl Hydrocarbon Receptor-Regulated Genes by Nickel

Aryl hydrocarbon receptor (AhR)-dependent enzymes are in- volved in the biotransformation of harmful xenobiotics into more easily excretable metabolites. Cross-talk between the AhR pathway and the hypoxia inducible factor-1 (cid:1) (HIF-1 (cid:1) ) pathway has been demonstrated previously, although the mechanism remains unclear and quite controversial. Because nickel is known to mimic hypoxia, we investigated the effects of short-term nickel exposure on AhR-dependent gene expression. Gene-chip analysis identified several AhR-dependent genes that are suppressed by exposure to nickel. Using Northern blots, we then confirmed that nickel can down-regulate both the basal and benzo[ a ]pyrene-inducible expression of AhR-dependent genes in mouse and human cell lines. Using a HIF-1 (cid:1) knockout cell line and 3-[2-[4-(bis-(4-fluorophenyl) methylene]-1-piperidinyl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone(R59949),whichblocksHIF-1 (cid:1) protein accumu-lation, we show HIF-1 (cid:1) –independent suppression of AhR-de-pendent genes by nickel. Desferrioxamine and hypoxia were also able to suppress the basal and inducible expression levels of AhR-regulated genes. Finally, dimethyloxalylglycine, an in- hibitor of Fe(II)- and 2-oxoglutarate–dependent dioxygenases also inhibited AhR-dependent expression in a HIF-1 (cid:1) –independent manner. Our data suggest that an Fe(II)-, oxoglutarate-, and oxygen-dependent enzyme may directly or indirectly be involved in the regulation of AhR-dependent transcriptional activity by nickel and other hypoxia-mimicking agents. 3-[2-[4-(bis-(4-fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone; MTT, 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide; polymerase chain reaction; GAPDH,
Inflammation and Atrial Fibrillation

There is accumulating evidence pointing to an important association between inflammation and atrial fibrillation (AF). Elevated plasma levels of several markers of the inflammatory cascade have been shown to predict future risk of AF. Inflammation is likely to represent a novel target for both the treatment and prevention of atrial fibrillation. I N T R O D U C T I O N Recent advances have raised the hope of effective pharmacological or non-pharmacological treatments of atrial fibrillation (AF), and of better understanding of the pathophysiological mechanisms involved in the initiation and persistence of the arrhythmia. The pathophysiology of AF is complex and multifactorial. The underlying etiology is likely different in different patient subpopulations. The development of AF leads to many structural and electrical changes contributing to its perpetuation [1]. Atrial fibrillation also confers a prothrombotic or hypercoagulable state, which may contribute to the risk of thromboembolism [2]. Acute phase response is an innate biological response to a disturbance in homeostasis (infection, inflammation, tissue injury, neoplasm, or immune disturbance). A local reaction at the site of injury or infection leads to an activation of cytokines, specifically interleukin-1 (IL-1), tumor necrosis factor-á (TNF-á), interleukin-6 (IL-6), and interferons. Cytokines then trigger systemic responses, which include leukocytosis; increases in glucocorticoid production; increases in erythrocyte sedimentation rate, fever, activation of complement and clotting cascades and an increase in plasma levels of acute phase proteins, C-reactive protein (CRP), serum amyloid A, fibrinogen, and other proteins [3]. C-reactive protein is one of the two most abundant acute phase reactants in humans: levels rapidly increase in the circulation as a result of either trauma or infection. Manufactured in the liver and deposited in damaged tissue, CRP is found in high levels in inflammatory fluids and in both the intimal layer of the atherosclerotic aortic artery and the foam cells within the lesions of atherosclerotic plaque [4,5]. C-reactive protein stimulates mononuclear cells to release tissue factor, a protein that is central to the initiation of coagulation reactions, complement activation, and the neutralization of plateletactivation factor. Together, these reactions promote a thrombotic response [6]. C-reactive protein has been traditionally thought of as a bystander marker of vascular inflammation, without playing a direct role in the inflammatory process. However, recent evidence suggests that CRP may contribute directly to the proinflammatory state [7,8]. An increased CRP plasma concentration is strongly associated with the CARDIOLOGY UPDATE 2006 2nd Department of Cardiology, Evangelismos General Hospital,
Improving communication of diagnostic radiology findings through structured reporting.

PURPOSE To compare the content, clarity, and clinical usefulness of conventional (ie, free-form) and structured radiology reports of body computed tomographic (CT) scans, as evaluated by referring physicians, attending radiologists, and radiology fellows at a tertiary care cancer center. MATERIALS AND METHODS The institutional review board approved the study as a quality improvement initiative; no written consent was required. Three radiologists, three radiology fellows, three surgeons, and two medical oncologists evaluated 330 randomly selected conventional and structured radiology reports of body CT scans. For nonradiologists, reports were randomly selected from patients with diagnoses relevant to the physician's area of specialization. Each physician read 15 reports in each format and rated both the content and clarity of each report from 1 (very dissatisfied or very confusing) to 10 (very satisfied or very clear). By using a previously published radiology report grading scale, physicians graded each report's effectiveness in advancing the patient's position on the clinical spectrum. Mixed-effects models were used to test differences between report types. RESULTS Mean content satisfaction ratings were 7.61 (95% confidence interval [CI]: 7.12, 8.16) for conventional reports and 8.33 (95% CI: 7.82, 8.86) for structured reports, and the difference was significant (P < .0001). Mean clarity satisfaction ratings were 7.45 (95% CI: 6.89, 8.02) for conventional reports and 8.25 (95% CI: 7.68, 8.82) for structured reports, and the difference was significant (P < .0001). Grade ratings did not differ significantly between conventional and structured reports. CONCLUSION Referring clinicians and radiologists found that structured reports had better content and greater clarity than conventional reports.
The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells

The long-lived latent HIV-1 reservoir is the major barrier for complete cure of Acquired Immune Deficiency Syndrome (AIDS). Here we report that a novel bromodomain and extraterminal domain (BET) inhibitor bromosporine which can broadly target BETs, is able to potently reactivate HIV-1 replication in different latency models alone and more powerful when combined with prostratin or TNF-α. Furthermore, the treatment with bromosporine induced HIV-1 full-length transcripts in resting CD4+ T cells from infected individuals with suppressive antiretroviral therapy (ART) ex vivo, with no obvious cytotoxicity or global activation of T cell. Finally, our data suggest that Tat plays a critical role in the bromosporine-mediated reactivation of latent HIV-1, which involved the increase of CDK9 T-loop phosphorylation. In summary, we found that the BET inhibitor bromosporine, alone or with other activators, might be a candidate for future HIV-1 eradication strategies.
The insertion sequence excision enhancer: A PrimPol‐based primer invasion system for immobilizing transposon‐transmitted antibiotic resistance genes

Evolutionary studies often identify genes that have been exchanged between different organisms and the phrase Lateral or Horizontal Gene Transfer is often used in this context. However, they rarely provide any mechanistic information concerning how these gene transfers might have occurred. With the astonishing increase in the number of sequences in public databases over the past two or three decades, identical antibiotic resistance genes have been identified in many different sequence contexts. One explanation for this would be that genes are initially transmitted by transposons which have subsequently decayed and can no longer be detected. Here, we provide an overview of a protein, IEE (Insertion Sequence Excision Enhancer) observed to facilitate high‐frequency excision of IS629 from clinically important Escherichia coli O157:H7 and subsequently shown to affect a large class of bacterial insertion sequences which all transpose using the copy‐out‐paste‐in transposition mechanism. Excision depends on both IEE and transposase indicating association with the transposition process itself. We review genetic and biochemical data and propose that IEE immobilizes genes carried by compound transposons by removing the flanking insertion sequence (IS) copies. The biochemical activities of IEE as a primase with the capacity to recognize DNA microhomologies and the observation that its effect appears restricted to IS families which use copy‐out‐paste‐in transposition, suggests IS deletion occurs by abortive transposition involving strand switching (primer invasion) during the copy‐out step. This reinforces the proposal made for understanding the widespread phenomenon loss of ISApl1 flanking mcr‐1 in the compound transposon Tn6330 which we illustrate with a detailed model. This model also provides a convincing way to explain the high levels of IEE‐induced precise IS excision.
Dynamics of SLC25A51 reveal preference for oxidized NAD+ and substrate led transport

SLC25A51 is a member of the mitochondrial carrier family (MCF) but lacks key residues that contribute to the mechanism of other nucleotide MCF transporters. Thus, how SLC25A51 transports NAD+ across the inner mitochondrial membrane remains unclear. To elucidate its mechanism, we use Molecular Dynamics simulations to reconstitute SLC25A51 homology models into lipid bilayers and to generate hypotheses to test. We observe spontaneous binding of cardiolipin phospholipids to three distinct sites on the exterior of SLC25A51's central pore and find that mutation of these sites impairs cardiolipin binding and transporter activity. We also observe that stable formation of the required matrix gate is controlled by a single salt bridge. We identify binding sites in SLC25A51 for NAD+ and show that its selectivity for NAD+ is guided by an electrostatic interaction between the charged nicotinamide ring in the ligand and a negatively charged patch in the pore. In turn, interaction of NAD+ with interior residue E132 guides the ligand to dynamically engage and weaken the salt bridge gate, representing a ligand‐induced initiation of transport.
Platelet-derived extracellular vesicles play an important role in platelet transfusion therapy

Abstract Extracellular vesicles (EVs) contain the characteristics of their cell of origin and mediate cell-to-cell communication. Platelet-derived extracellular vesicles (PEVs) not only have procoagulant activity but also contain platelet-derived inflammatory factors (CD40L and mtDNA) that mediate inflammatory responses. Studies have shown that platelets are activated during storage to produce large amounts of PEVs, which may have implications for platelet transfusion therapy. Compared to platelets, PEVs have a longer storage time and greater procoagulant activity, making them an ideal alternative to platelets. This review describes the reasons and mechanisms by which PEVs may have a role in blood transfusion therapy. Plain Language Summary What is the context? Platelet transfusion is a treatment that can be effective in preventing bleeding and reducing the amount of bleeding. However, platelet transfusion may cause some unsatisfactory effects for patients, such as adverse transfusion reactions and poor prognosis in cancer patients. These benefits and harms caused by platelet transfusion may be related to PEVs. With the prolongation of storage time during the shelf life of platelets, PEVs were continuously released and the therapeutic effect of platelet components seems to get worse. What is new? This article not only reviews the evidence for PEVs plays a role in blood transfusion therapy but also introduces the mechanism of PEVs in platelet storage lesion and the common methods of isolation and characterization of PEVs. What is the impact? It is necessary to improve the method of isolation and purification of PEVs, to increase the purity of PEVs isolation, and to further demonstrate the potential of PEVs to replace platelets. Further research into the mechanisms by which platelets and PEVs affect the prognosis of cancer patients is required.
How Subjective Idea Valuation Energizes and Guides Creative Idea Generation

What drives us to search for creative ideas, and why does it feel good to find one? While previous studies demonstrated the positive influence of motivation on creative abilities, how reward and subjective values play a role in creativity remains unknown. This study proposes to characterize the role of individual preferences (how people value ideas) in creative ideation via behavioral experiments and computational modeling. Using the Free Generation of Associates Task coupled with rating tasks, we demonstrate the involvement of valuation processes during idea generation: preferred ideas are provided faster. We found that valuation depends on the adequacy and originality of ideas and guides response selection and creativity. Finally, our computational model correctly predicts the speed and quality of human creative responses, as well as interindividual differences in creative abilities. Altogether, this model introduces the mechanistic role of valuation in creativity. It paves the way for a neurocomputational account of creativity mechanisms. Public Significance Statement This study addresses the role of individual preferences in creativity. It demonstrates that preferences for ideas energize creative idea production: the more participants like their ideas, the faster they provide them. Moreover, preferences rely on an equilibrium between the adequacy and originality of ideas and vary across individuals. This study introduces a computational model which incorporates individual preferences and that correctly predicts the speed and quality of responses in a creative idea generation task, as well as inter-individual differences in creative abilities. Comparison of several versions of this model demonstrated that preferences guide the selection of creative responses.
Ericoid shrub encroachment shifts aboveground–belowground linkages in three peatlands across Europe and Western Siberia

In northern peatlands, reduction of Sphagnum dominance in favour of vascular vegetation is likely to influence biogeochemical processes. Such vegetation changes occur as the water table lowers and temperatures rise. To test which of these factors has a significant influence on peatland vegetation, we conducted a 3‐year manipulative field experiment in Linje mire (northern Poland). We manipulated the peatland water table level (wet, intermediate and dry; on average the depth of the water table was 17.4, 21.2 and 25.3 cm respectively), and we used open‐top chambers (OTCs) to create warmer conditions (on average increase of 1.2°C in OTC plots compared to control plots). Peat drying through water table lowering at this local scale had a larger effect than OTC warming treatment per see on Sphagnum mosses and vascular plants. In particular, ericoid shrubs increased with a lower water table level, while Sphagnum decreased. Microclimatic measurements at the plot scale indicated that both water‐level and temperature, represented by heating degree days (HDDs), can have significant effects on the vegetation. In a large‐scale complementary vegetation gradient survey replicated in three peatlands positioned along a transitional oceanic–continental and temperate–boreal (subarctic) gradient (France–Poland–Western Siberia), an increase in ericoid shrubs was marked by an increase in phenols in peat pore water, resulting from higher phenol concentrations in vascular plant biomass. Our results suggest a shift in functioning from a mineral‐N‐driven to a fungi‐mediated organic‐N nutrient acquisition with shrub encroachment. Both ericoid shrub encroachment and higher mean annual temperature in the three sites triggered greater vascular plant biomass and consequently the dominance of decomposers (especially fungi), which led to a feeding community dominated by nematodes. This contributed to lower enzymatic multifunctionality. Our findings illustrate mechanisms by which plants influence ecosystem responses to climate change, through their effect on microbial trophic interactions.
Evaluation of Predicting Factors Affecting Sperm Retrieval in Patients with Klinefelter Syndrome: A Prospective Study

Background: This study aimed to evaluate the predicting factors affecting sperm retrieval. We prospectively assessed the relationship between sonographic and microdissection testicular sperm extraction (mTESE) findings in Klinefelter syndrome (KS). Materials and Methods: In this prospective study, 44 azoospermic men with 47, XXY karyotypes participated in this study. In order to evaluate the amount of blood supply in different parts of testicular tissue, a doppler ultra-sonographic was performed. Also, for the detection of sperm in this group mTESE technique was performed. Results: The age average of positive mTESE and negative mTESE groups was 29.4 and 33.6 years, respectively. By comparing the testicle volume (based on the data obtained from the clinical examinations conducted by the urologist) it was determined that there is no significant difference between mTESE positive and negative groups. Folliclestimulating hormone (FSH) levels in men with negative mTESE (P=0.03) and testosterone levels in men with positive mTESE significantly increased (P=0.017). The overall rate of testis vascularity was significantly higher in the positive mTESE group than in the negative mTESE group. The clinical pregnancy rate in positive mTESE men was 9% per cycle, 16.6% per embryos were transferred (ET), and 12.5% per cycle. Conclusion: Totally, our observation indicated that there is not a significant relationship between sonographic and mTESE results in KS patients. However, more investigations with bigger sample Size can be useful to validate our results.