question:You will be shown biomedical passages and your task is to the answer the provided question. Provide a concise and accurate response and do not include any additional text in the response other than the answer.Question: Which member of the human mycobiota is associated to atherosclerosis?Context: Interestingly, the relative abundance of Mucor racemosus was negatively associated both with FRS and cIMT.Variable importance in projection scores showed that M. racemosus abundance had the same impact in the model as waist-to-hip ratio, high-density lipoprotein-cholesterol, fasting triglycerides or fasting glucose, suggesting that M. racemosus relative abundance in the gut may be a relevant biomarker for cardiovascular risk.

question:You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: ["Disease"].Please return the output as a JSON object of the format: {"Disease" : ["COVID-19", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].Only output the JSON object and do not include any additional text.Abstract:Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) has been shown to play a major role in the regulation of T cell activation. Its membrane expression is highly regulated by endocytosis and trafficking through the secretory lysosome pathway. Chediak-Higashi syndrome (CHS) is an inherited disorder caused by mutations in the lysosomal trafficking regulator gene, LYST. It results in defective membrane targeting of the proteins present in secretory lysosomes, and it is associated with a variety of features, including a lymphoproliferative syndrome with hemophagocytosis. The murine equivalent of CHS, beige mice, present similar characteristics but do not develop the lymphoproliferative syndrome. We show herein that CTLA-4 is present in enlarged, abnormal vesicles in CHS T cells and is not properly expressed at the cell surface after T cell activation, whereas its surface expression is not impaired. It is therefore proposed that the defective surface expression of CTLA-4 by CHS T cells is involved in the generation of lymphoproliferative disease. This observation may provide insight into the role of CTLA-4 in humans..

question:You will be provided with the titles and abstracts of a collection of medical RCT reports studying a clinical question -- for instance, the efficacy of an intervention on some medical outcome. Please write a few sentences synthesizing the findings of these reports, which could serve as a conclusion section for a systematic review article. Your response should not include any other text. The RCT reports are below.Title 1:A memory assessment technique for use in geriatric psychopharmacology: drug efficacy trial with naftidrofuryl.Abstract 1:This study was conducted to compare an automated test of paced stimulus material (Sperling's Perceptual Trace, SPT) with several other standard memory scales. Sixty patients with mild senile organic brain syndrome were divided into two groups of 30; one group was treated for 90 days with 300 mg daily of naftidrofuryl (Praxilene), and the other group received placebo. The patients were tested before treatment and at 30, 60 and 90 days after the beginning of treatment. The data indicated that the SPT indirectly assesses short-term memory, is resistant to practice effects, and is drug-sensitive. It is suggested that the SPT might become the test of choice in the indirect assessment of short-term memory in the elderly.Title 2:[Efficacy and tolerance of long-term naftidrofuryl treatment of patients with senile dementia. Controlled study versus placebo].Abstract 2:nanTitle 3:Efficacy of naftidrofuryl in patients with vascular or mixed dementia: results of a multicenter, double-blind trial.Abstract 3:Dementia is a cerebral disorder resulting in a progressive deterioration of intellectual function that compromises the patient's ability to function. The diagnostic criteria for dementia are primarily clinical and are based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The Hachinski score and computed tomography of the brain help distinguish between degenerative and vascular dementias. This study examined the efficacy of naftidrofuryl in patients with vascular or mixed dementia. This multicenter, randomized, double-blind study compared naftidrofuryl 600 mg/d with placebo for 1 year in patients with vascular or mixed dementia. A preliminary 2-month washout period allowed selection of patients who were compliant with treatment. The end point was change in the scores on the Alzheimer Disease Assessment Scale cognitive subscale and the Mini-Mental State Examination. Eighty-four patients were assessable on an intent-to-treat basis, and 74 were assessable for the per-protocol analysis (on-treatment). Statistically significant improvements in cognitive and global function were observed in patients receiving naftidrofuryl. Naftidrofuryl was well tolerated, and produced no clinically significant abnormalities in laboratory test results. The results of this study suggest that naftidrofuryl is effective and well tolerated in treating the symptoms of vascular and mixed dementia.Title 4:Naftidrofuryl in the treatment of vascular dementia.Abstract 4:The design of this study was based on the European guidelines for the treatment of Alzheimer's disease. After a placebo run-in period of 4 weeks, patients with a diagnosis of vascular dementia (VaD) were randomised to receive either 400 mg naftidrofuryl/day, 600 mg naftidrofuryl/day or placebo for 6 months. The patients were assessed using the ADAS-cog, the SCAG, the NOSGER and the CGI item 2 scale. The primary analysis was undertaken on the ITT population. At the end of the study, significantly more patients in the treatment groups showed no deterioration on both ADAS-cog and SCAG scales compared with placebo (400 mg p = 0.005, 600mg p = 0.015). There were also significant differences between the active and placebo groups for the individual scales. This study has demonstrated that treatment with naftidrofuryl can slow the rate of deterioration of patients with vascular dementia.Title 5:Efficacy of naftidrofuryl in patients with moderate senile dementia.Abstract 5:In a controlled double-blind study, 78 patients with moderate senile dementia were randomly assigned to 3-months' treatment with 200 mg naftidrofuryl twice daily in slow-release form or with placebo. The patients were selected on the basis of the EACG (Echelle d'Appréciation Clinique en Gériatrie), which was also used as main criterion for confirmatory analysis of the efficacy of naftidrofuryl. A further main criterion was the SGRS (Stockton Geriatric Rating Scale). Secondary criteria examined were visual memory as tested in the Benton test, verbal memory as tested in the Rey test and numerical memory as tested in the digit-span test. The patients' concentration was tested in the Zazzo test. The tests were performed before the patients were admitted to the study and after 1 and 3-months' treatment. Confirmatory analysis of the primary criteria showed a significant treatment difference in favour of naftidrofuryl in the form of improvement in the global symptoms of senile dementia both in the EACG and in the SGRS, the scores in the naftidrofuryl group improving by 15% compared with only 5% in the placebo group. This was paralleled by a significant improvement in visual and verbal memory in the naftidrofuryl group in comparison with placebo. The naftidrofuryl patients also showed a greater improvement in concentration than the placebo group. One patient in the naftidrofuryl group suffered briefly from gastro-intestinal symptoms. There were no changes in routine laboratory parameters studied.Title 6:[Naftidrofuryl in patients with multi-infarct dementia and Alzheimer's disease].Abstract 6:nanTitle 7:A cognitive impairment scale applicable to verbal samples and its possible use in clinical trials in patients with dementia [proceedings].Abstract 7:nan

question:You will be presented a sentence from biomedical research text. Extract all terms that correspond to chemical entities of biological interest (ChEBI).Return your identified terms in a JSON array, formatted like this: ["Entity1", "Entity2", ...].If no such entities are detected, respond by providing an empty JSON array [].Biomedical context:6B.

question:You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.Title: High-resolution transcriptional dissection of in vivo Atoh1-mediated hair cell conversion in mature cochleae identifies Isl1 as a co-reprogramming factor}Article:Abstract:In vivo direct conversion of differentiated cells holds promise for regenerative medicine; however, improving the conversion efficiency and producing functional target cells remain challenging. Ectopic Atoh1 expression in non-sensory supporting cells( SCs) in mouse cochleae induces their partial conversion to hair cells( HCs) at low efficiency. Here, we performed single-cell RNA sequencing of whole mouse sensory epithelia harvested at multiple time points after conditional overexpression of Atoh1. Pseudotemporal ordering revealed that converted HCs( cHCs) are present along a conversion continuum that correlates with both endogenous and exogenous Atoh1 expression. Bulk sequencing of isolated cell populations and single-cell qPCR confirmed 51 transcription factors, including Isl1, are differentially expressed among cHCs, SCs and HCs. In transgenic mice, co-overexpression of Atoh1 and Isl1 enhanced the HC conversion efficiency. Together, our study shows how high-resolution transcriptional profiling of direct cell conversion can identify co-reprogramming factors required for efficient conversion.Introduction:During development, pluripotent stem cells follow lineage-specific pathways to differentiate into mature cells that can be converted back to pluripotent cells by defined transcription factors( TFs)[1]. In addition, direct lineage conversion( also termed transdifferentiation) between differentiated cells has been demonstrated in heart, pancreas, brain, and other tissues through the use of defined TFs[2–5] or pharmacologic agents[6]. Such conversions have provided a deeper mechanistic understanding of development and hold promise for regenerative medicine. Several studies have used single-cell RNA-seq to identify distinct intermediate conversion states, providing valuable insights into how to improve the efficiency and complete the direct conversions[4, 7, 8]. The cells of the mouse inner-ear cochlear sensory epithelium( organ of Corti) are post-mitotic after birth and exhibit limited spontaneous regeneration that is only present during the first week after birth[9–11]. Atoh1, a lineage-specific TF for sensory hair cells( HCs), directly converts non-sensory supporting cells( SCs) to HCs in cochlear explant culture, as well as in vivo[12–15]. The current model is that ectopic Atoh1 induces the expression of endogenous Atoh1 in SCs to initiate the conversion. This Atoh1-mediated HC conversion is analogous to the natural HC regeneration in chicken inner ears or mammalian vestibular organs[16, 17]. However, the Atoh1-converted HCs( cHCs) in mouse cochleae exhibit immature morphology and do not express several terminal differentiation markers( e. g., Slc26a5 encoding prestin and Ocm encoding oncomodulin). In addition, the process is inefficient, with conversion rates of 6%–20%[13, 14]. Consequently, a more precise understanding of the molecular events underlying Atoh1-induced HC conversion is needed to identify additional factors required for improving the efficiency and completion of the conversion. In this study, we performed unbiased transcriptional profiling of all cells present in the organ of Corti during Atoh1-mediated SC-to-HC conversion at multiple time points in vivo. This high-resolution transcriptomic analysis revealed new mechanisms of HC conversion in vivo and identified co-reprogramming factors.Discussion:Based on our multi-faceted transcriptome profiling, our cHCs start with donor SCs( P12) when Atoh1-HA is ectopically expressed, gradually decrease expression of many SC-enriched genes, concomitantly gain HC signatures, and eventually reach the cHC3 state that closely resembles neonatal HCs( i. e., P7 OHCs). These results are consistent with our previous reports using morphological and immunostaining criteria[14, 21]. In >125 individual cHCs and >161 SCs/OHCs at three independent time points( P12, P26 and P33), the cHC conversion is a continuum, a conclusion also supported by our bulk RNA-seq and single-cell qPCR analyses. The pseudotemporal separation of the conversion enabled the logical identification of TFs that are required at different stages of conversion. Interestingly, we discover two clusters of early transition states( cHC1/2) that transiently express different sets of TF genes that can potentially contribute to the initial conversion from SCs at P12. By identifying differentially expressed TF genes between cHC3 and mature OHCs, we also list TFs that can presumably promote the completion of conversion. By gene network analysis, we discover the key TFs for conversion, including Atoh1, Pou4f3 and their closely correlated TFs, several of which have been previously demonstrated to contribute to SC-to-HC conversion[13, 14, 21, 39]. For example, Pou4f3 functionally promotes Atoh1-mediated conversion in vitro( together with Gfi1)[39] and in vivo[21], while GATA3 plays a key role in the Atoh1-mediated conversion in adult cochleae in vivo[21]. Future analyses of our high-resolution profiling can provide further insight into Atoh1-mediated conversion. For example, conversion paths are dependent on the starting donor cell’s genetic and epigenetic states, driving factors, and environment[2, 5, 40]. It is possible that distinct subpopulations of SCs provide the appropriate cellular context where Atoh1 has access to the required target loci to induce further conversion. Further work is needed to determine how closely early cHCs( i. e., cHC1/2) resemble otic progenitors, bypassing potentially harmful( i. e., tumorigenic) aspects of the progenitor phenotype. Along with the revealed continuous process of conversion( from SC1 to cHC3), we also found that the expression of endogenous Atoh1 is progressively upregulated, with the lowest expression in the SC1 state and the highest expression in the cHC3 state. Such upregulation of endogenous Atoh1 is attributed to the ectopic expression of Atoh1-HA and the transcriptional autoregulation of the endogenous Atoh1[31]. Interestingly, Atoh1-HA is also progressively upregulated during conversion from SC1 to cHC3. In fact, endogenous Atoh1 and transgenic Atoh1-HA were highly correlated in >125 cHCs analyzed. It is commonly assumed that the CAG promoter drives constant high levels of gene expression in all cells at all times; however, this may not be true in the organ of Corti. In support of this, tdTomato reporter expression driven by the CAG promoter at the ROSA locus also exhibits strikingly different intensities between IHCs and OHCs at P76( S3B Fig). It is possible that both the CAG promoter for Atoh1-HA and the endogenous Atoh1 promoter are subject to transcriptional regulation by some common transcriptional or epigenetic factors[41]. It is also possible that Atoh1 and Atoh1-HA mRNAs are stabilized by common but unknown RNA binding proteins or miRNAs. Interestingly, Dicer mutant mice exhibited immature hair bundle morphology strikingly similar to that in Atoh1-HA-driven converted HCs[21, 42], linking miRNAs to Atoh1 mRNA stability. For most direct reprogramming, multiple TFs function together, simultaneously or consecutively, either in the initiation stage or the later stage, to determine the cell fate and to induce efficient and complete conversion[2–5]. Thus, it is critical to identify TFs that improve Atoh1-mediated conversion. Here we have identified and validated 52 TF genes, including Atoh1, that are differentially expressed in SCs, cHCs, and OHCs. Notably, of these 52 TFs, Pou4f3 functionally promotes Atoh1-mediated conversion in vitro( together with Gfi1)[39] and in vivo[21] or by itself promotes conversion in vivo[21]. Interestingly, several TFs among the 52 are involved in development and cell fate reprogramming. For example, Isl1 is critical for pacemaker cell differentiation in the heart[43], and for motor neuron differentiation[44]. Several TFs( Isl1, Tub, Zbtb38, Zfp827, Aff3, Mixip and Zfp532) have been shown to be involved in pacemaker cell conversion in the heart[43]. Moreover, overexpression of Lhx3 in cochlear nonsensory cells is suggested to lead to Isl1 suppression[45]. Isl1 is also co-expressed with Atoh1 during early cochlear development[46]. Here we provided ex vivo and in vivo evidence that Isl1 indeed synergistically enhances Atoh1-mediated conversion in the cochlea. However, it remains unknown how Isl1 promotes Atoh1-mediated conversion. Notably, by forming complexes with different TFs( Lhx3 vs Phox2a), Isl1 can program ESCs to distinct cell identities( spinal vs. cranial motor neurons)[44, 47] by turning on variable groups of target genes determined by its binding partners. Thus, it will be important to identify the specific Isl1 binding complex in Atoh1-induced conversion. Moreover, future studies( e. g. single-cell RNA-seq and electrophysiology) on the Atoh1 and Isl1-converted HCs are also needed to molecularly and biologically characterize these cells to examine whether Isl1 also promotes HC maturation in vivo. Nonetheless, these results for Isl1 ex vivo and in vivo undoubtedly validate our single-cell transcriptomic analyses and identify 51 TFs that can promote Atoh1-mediated conversion in vivo. SC-to-HC direct conversion is initially predominant in chicken HC regeneration that also starts with upregulation of Atoh1 in SCs[48] where the initial nuclear migration and other morphological cellular transformation are also similar to what we have characterized in our Atoh1-HA ectopic expression cochlear models[14, 21]. These parallels strengthen the notion that Atoh1-mediated HC conversion in the mature cochlea recapitulates the initial phases of naturally occurring HC conversion in non-mammalian species[48] and mammalian utricles[16]. Of note, our Atoh1-mediated SC-to-HC conversion path is remarkably similar to those reprogramming paths described in other regenerative systems. Ascl1-driven reprogramming of mouse embryonic fibroblast( MEF) cells to induced neurons( iN) in vitro exhibited a continuous conversion path nearly identical to the Atoh1-mediated conversion path[8]. Both Atoh1 and Ascl1 appear to act in a similar manner where donor cells overcome threshold barriers to initiate simultaneous upregulation of target cell fate genes and downregulation of donor cell fate genes. Moreover, in the MEF-to-iN conversion in vitro, additional reprogramming factors( Brn2 and Mytl1) further prevented competing myogenic programs and/or reversal to the initial donor state. While in our Atoh1-mediated SC-to-HC conversion, additional factors may play similar roles as Brn2 and Mytl1; the 51 TFs identified here may also benefit other regenerative systems by improving their efficiency and completion. Together, our studies represent a major step towards understanding cochlear HC regeneration in vivo, with the potential to further improve the ongoing ATOH1 gene therapy in the clinic for patients with hearing loss. More importantly, our approach provides a valued strategy for better studying cochlea and other regenerative systems where conversion efficiency and completion are also central challenges.

question:Given an abstract from a research paper, your task is to identify and label relationships between chemical compounds and genes mentioned in the abstract.The relationship type must be one of ['DOWNREGULATOR', 'SUBSTRATE', 'INDIRECT-REGULATOR', 'PART-OF', 'MODULATOR-ACTIVATOR', 'REGULATOR', 'INHIBITOR', 'COFACTOR', 'UPREGULATOR', 'ACTIVATOR', 'ANTAGONIST', 'NOT', 'INDIRECT-DOWNREGULATOR', 'SUBSTRATE_PRODUCT-OF', 'INDIRECT-UPREGULATOR', 'AGONIST', 'PRODUCT-OF', 'MODULATOR', 'DIRECT-REGULATOR', 'UNDEFINED', 'AGONIST-INHIBITOR', 'AGONIST-ACTIVATOR', 'MODULATOR-INHIBITOR'].Please format your output as a JSON array. Each entry in the array should express a single relation, formatted as ["<Entity_A>", "<RELATION_A_B>", "<Entity_B>"]. If no relations can be found, please output an empty JSON array [].Abstract:Efficient MRI labeling of endothelial progenitor cells: Design of thiolated surface stabilized superparamagnetic iron oxide nanoparticles. The aim of this study was to design thiolated surface stabilized superparamagnetic iron oxide nanoparticles (TSS-SPIONs) for efficient internalization with high MRI sensitivity. TSS-SPIONs were developed by chelation between thiolated chitosan-thioglycolic acid (chitosan-TGA) hydrogel and iron ions (Fe (2+) /Fe (3 +)). Likely, unmodified chitosan hydrogel SPIONs (UC-SPIONs) and uncoated SPIONs were used as control. Moreover, TSS-SPIONs were investigated regarding to their iron core size, hydrodynamic diameter, zeta potential, iron contents, molar relaxivities (r1 and r2), and cellular internalization. TSS-SPIONs demonstrated an iron oxide core diameter (crystallite size by XRD) of 3.1±0.02 nm, a hydrodynamic diameter of 94±20 nm, a zeta potential of + 21±5mV, and an iron content of 3.6±0.9mg/mL. In addition, internalization of TSS-SPIONs into human endothelial progenitor cells (EPC) from umbilical cord blood was more than threefold and 17-fold higher in contrast to UC-SPIONs and SPIONs, respectively. With twofold lower incubation iron concentration of TSS-SPIONs, more than threefold higher internalization was achieved as compared to Resovist ®. Also, cell viability of more than 90% was observed in the presence of TSS-SPIONs after 24h. The molar MR relaxivities (r2) value at 1.5 T was threefold higher than that of Resovist ® and demonstrated that TSS-SPIONs have the potential as very effective T2 contrast-enhancement agent. According to these findings, TSS-SPIONs with efficient internalization, lower cytotoxicity, and high MRI sensitivity seem to be promising for cell tracking.