Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional characterization of the biogenic amine transporters on human macrophages

Monocyte-derived macrophages (MDMs) are key players in tissue homeostasis and diseases regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling in and around immune cells remain nebulous. In the CNS, biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown that macrophages express these transporters, relatively little is known of their function in these cells. To address these knowledge gaps, we investigated the function of norepinephrine transporter (NET) and dopamine transporter (DAT) on human MDMs. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured MDMs, but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immunomodulatory mechanism in response to LPS. LPS induced reverse transport of dopamine through DAT, engaging an autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the proinflammatory response to LPS. Our data introduce a potential role for DAT in the regulation of innate immunity.
The Efficacy of High-Volume Evacuators and Extraoral Vacuum Aspirators in Reducing Aerosol and Droplet in Ultrasonic Scaling Procedures during the COVID-19 Pandemic

Abstract Objective SARS-CoV-2 can be carried by aerosols and droplets produced during dental procedures, particularly by the use of high-speed handpieces, air-water syringes, and ultrasonic scalers. High-volume evacuators (HVEs) and extraoral vacuum aspirators (EOVAs) reduce such particles. However, there is limited data on their efficacy. This study aimed to determine the efficacy of HVE and EOVA in reducing aerosols and droplets during ultrasonic scaling procedures. Materials and Methods Three ultrasonic scaling simulations were conducted on mannequins: 1. saliva ejector (SE) was used alone (control); 2. SE was used in combination with HVE; and 3. SE was used in combination with HVE and EOVA. Paper filters were placed on the operator's and assistant's face shields and bodies, and the contamination of aerosols and droplets was measured by counting blue spots on the paper filters. Statistical Analysis All data were analyzed for normality using the Kolmogorov–Smirnov test. The differences between each method were analyzed using a two-way ANOVA, followed by a posthoc test. The differences were considered statistically significant when p < 0.05 Result Using HVE and EOVA reduced aerosols and droplets better than using SE alone or SE and HVE: the posthoc test for contamination revealed a significant difference (p < 0.01). The assistant was subjected to greater contamination than the operator during all three ultrasonic scaling procedures. Conclusion The usage of HVE and EOVA significantly reduced aerosols and droplets compared with using SE solely. Using these techniques together could prevent the transmission of airborne disease during dental cleanings, especially COVID-19. Further studies of aerosol-reducing devices are still needed to ensure the safety of dental workers and patients.
Dendritic Morphology of an Inhibitory Retinal Interneuron Enables Simultaneous Local and Global Synaptic Integration

Amacrine cells, inhibitory interneurons of the retina, feature synaptic inputs and outputs in close proximity throughout their dendritic trees, making them notable exceptions to prototypical somato-dendritic integration with output transmitted via axonal action potentials. The extent of dendritic compartmentalization in amacrine cells with widely differing dendritic tree morphology, however, is largely unexplored. Combining compartmental modeling, dendritic Ca2+ imaging, targeted microiontophoresis and multielectrode patch-clamp recording (voltage and current clamp, capacitance measurement of exocytosis), we investigated integration in the AII amacrine cell, a narrow-field electrically coupled interneuron that participates in multiple, distinct microcircuits. Physiological experiments were performed with in vitro slices prepared from retinas of both male and female rats. We found that the morphology of the AII enables simultaneous local and global integration of inputs targeted to different dendritic regions. Local integration occurs within spatially restricted dendritic subunits and narrow time windows and is largely unaffected by the strength of electrical coupling. In contrast, global integration across the dendritic tree occurs over longer time periods and is markedly influenced by the strength of electrical coupling. These integrative properties enable AII amacrines to combine local control of synaptic plasticity with location-independent global integration. Dynamic inhibitory control of dendritic subunits is likely to be of general importance for amacrine cells, including cells with small dendritic trees, as well as for inhibitory interneurons in other regions of the CNS. SIGNIFICANCE STATEMENT Our understanding of synaptic integration is based on the prototypical morphology of a neuron with multiple dendrites and a single axon at opposing ends of a cell body. Many neurons, notably retinal amacrine cells, are exceptions to this arrangement, and display input and output synapses interspersed along their dendritic branches. In the large dendritic trees of some amacrine cells, such arrangements can give rise to multiple computational subunits. Other amacrine cells, with small dendritic trees, have been assumed to operate as single computational units. Here, we report the surprising result that despite a small dendritic tree, the AII amacrine cell simultaneously performs local integration of synaptic inputs (over smaller dendritic subregions) and global integration across the entire cell.
The Hinge Region of the Israeli Acute Paralysis Virus Internal Ribosome Entry Site Directs Ribosomal Positioning, Translational Activity, and Virus Infection

Viruses must use the host cell machinery to direct viral protein expression for productive infection. One such mechanism is an internal ribosome entry site that can directly recruit host cell machinery. In this study, we have identified a novel sequence in an IRES that provides insight into the mechanism of viral gene expression. Specifically, this novel sequence promotes viral IRES activity by directly guiding the host cell machinery to start gene expression at a specific site. ABSTRACT All viruses must usurp host ribosomes for viral protein synthesis. Dicistroviruses utilize an intergenic region internal ribosome entry site (IGR IRES) to directly recruit ribosomes and mediate translation initiation from a non-AUG start codon. The IGR IRES adopts a three-pseudoknot structure that comprises a ribosome binding domain of pseudoknot II and III (PKII and PKIII), and a tRNA-like anticodon domain (PKI) connected via a short, one to three nucleotide hinge region. Recent cryo-EM structural analysis of the dicistrovirus Taura syndrome virus (TSV) IGR IRES bound to the ribosome suggests that the hinge region may facilitate translocation of the IRES from the ribosomal A to P site. In this study, we provide mechanistic and functional insights into the role of the hinge region in IGR IRES translation. Using the honeybee dicistrovirus, Israeli acute paralysis virus (IAPV), as a model, we demonstrate that mutations of the hinge region resulted in decreased IRES-dependent translation in vitro. Toeprinting primer extension analysis of mutant IRESs bound to purified ribosomes and in rabbit reticulocyte lysates showed defects in the initial ribosome positioning on the IRES. Finally, using a hybrid dicistrovirus clone, mutations in the hinge region of the IAPV IRES resulted in decreased viral yield. Our work reveals an unexpected role of the hinge region of the dicistrovirus IGR IRES coordinating the two independently folded domains of the IRES to properly position the ribosome to start translation. IMPORTANCE Viruses must use the host cell machinery to direct viral protein expression for productive infection. One such mechanism is an internal ribosome entry site that can directly recruit host cell machinery. In this study, we have identified a novel sequence in an IRES that provides insight into the mechanism of viral gene expression. Specifically, this novel sequence promotes viral IRES activity by directly guiding the host cell machinery to start gene expression at a specific site.
Intracochlear New Fibro-Ossification and Neuronal Degeneration Following Cochlear Implant Electrode Translocation: Long-Term Histopathological Findings in Humans

Objective: We aim to assess the histopathology of human temporal bones (TBs) with evidence of cochlear implantation (CI) electrode scalar translocation. Study Design: Otopathology study. Setting: Otopathology laboratory. Patients: TBs from patients who had a history of CI and histopathological evidence of interscalar translocation. Specimens with electrode placed entirely within the ST served as controls. Intervention: Histopathological assessment of human TBs. Main Outcome Measures: TBs from each patient were harvested postmortem and histologically analyzed for intracochlear changes in the context of CI electrode translocation and compared to controls. Intracochlear new fibro-ossification, and spiral ganglion neuron (SGN) counts were assessed. Postoperative word recognition scores (WRS) were also compared. Results: Nineteen human TBs with electrode translocation and eight controls were identified. The most common site of translocation was the ascending limb of the basal turn (n = 14 TBs). The average angle of insertion at the point of translocation was 159° ± 79°. Eighteen translocated cases presented moderate fibroosseous changes in the basal region of the cochlea, extending to the translocation point and/or throughout the electrode track in 42%. Lower SGN counts were more pronounced in translocated cases compared to controls, with a significant difference for segment II (p = 0.019). Although final postoperative hearing outcomes were similar between groups, translocated cases had slower rate of improvement in WRS (p = 0.021). Conclusions: Cochlear implant electrode translocation was associated with greater fibroosseous formation and lower SGN population. Our findings suggest that scalar translocations may slow the rate of improvement in WRS overtime as compared to atraumatic electrode insertions. Level of evidence: IV.
The rhipidoglossan radula: Radular morphology and formation in Nerita litterata Gmelin, 1791 (Neritimorpha, Neritidae)

The rhipidoglossan radula, consisting of numerous teeth in each transverse row, is characteristic of phylogenetically distant groups of gastropods, including Vetigastropoda, Neritimorpha and ‘lower’ Heterobranchia. Previous studies have revealed the main patterns in the formation of the rhipidoglossan radula of vetigastropods, the main feature of which is the division of the formation zone into two horns, where marginal teeth are formed by a multilayered epithelium (odontoblasts). This work is devoted to the study of the formation of the rhipidoglossan radula of Nerita litterata using light and electron microscopy. The data obtained show that, despite the different external morphology of the radular sac of neritids and vetigastropods, the radular sac of N. litterata, like that of vetigastropods, is divided into two parts, in which the marginal teeth are similarly formed by odontoblasts located in more than one layer. It seems probable that this complex, three‐dimensional structure of the formation zone is associated with a broad radula with numerous elongate marginal teeth and could be characteristic of other gastropods with this type of radula. Additional supporting rods located along the odontoblasts and consisting of vacuolated cells were first discovered in Nerita.
ICP22 of Herpes Simplex Virus 1 Decreases RNA Polymerase Processivity

The longstanding observation that ICP22 reduces RNA polymerase II (Pol II) serine 2 phosphorylation, which initiates transcriptional elongation, is puzzling because this phosphorylation is essential for viral replication. The current study helps explain this apparent paradox because it demonstrates significant advantages in negatively regulating transcriptional elongation, including the reduction of antisense and intergenic transcription. ABSTRACT To determine the role of ICP22 in transcription, we performed precise nuclear run-on followed by deep sequencing (PRO-seq) and global nuclear run-on with sequencing (GRO-seq) in cells infected with a viral mutant lacking the entire ICP22-encoding α22 (US1/US1.5) gene and a virus derived from this mutant bearing a restored α22 gene. At 3 h postinfection (hpi), the lack of ICP22 reduced RNA polymerase (Pol) promoter proximal pausing (PPP) on the immediate early α4, α0, and α27 genes. Diminished PPP at these sites accompanied increased Pol processivity across the entire herpes simplex virus 1 (HSV-1) genome in GRO-seq assays, resulting in substantial increases in antisense and intergenic transcription. The diminished PPP on α gene promoters at 3 hpi was distinguishable from effects caused by treatment with a viral DNA polymerase inhibitor at this time. The ICP22 mutant had multiple defects at 6 hpi, including lower viral DNA replication, reduced Pol activity on viral genes, and increased Pol activity on cellular genes. The lack of ICP22 also increased PPP release from most cellular genes, while a minority of cellular genes exhibited decreased PPP release. Taken together, these data indicate that ICP22 acts to negatively regulate transcriptional elongation on viral genes in part to limit antisense and intergenic transcription on the highly compact viral genome. This regulatory function directly or indirectly helps to retain Pol activity on the viral genome later in infection. IMPORTANCE The longstanding observation that ICP22 reduces RNA polymerase II (Pol II) serine 2 phosphorylation, which initiates transcriptional elongation, is puzzling because this phosphorylation is essential for viral replication. The current study helps explain this apparent paradox because it demonstrates significant advantages in negatively regulating transcriptional elongation, including the reduction of antisense and intergenic transcription. Delays in elongation would be expected to facilitate the ordered assembly and functions of transcriptional initiation, elongation, and termination complexes. Such limiting functions are likely to be important in herpesvirus genomes that are otherwise highly transcriptionally active and compact, comprising mostly short, intronless genes near neighboring genes of opposite sense and containing numerous 3′-nested sets of genes that share transcriptional termination signals but differ at transcriptional start sites on the same template strand.
Distinct transcription kinetics of pluripotent cell states

Mouse embryonic stem cells (mESCs) can adopt naïve, ground, and paused pluripotent states that give rise to unique transcriptomes. Here, we use transient transcriptome sequencing (TT‐seq) to define both coding and non‐coding transcription units (TUs) in these three pluripotent states and combine TT‐seq with RNA polymerase II occupancy profiling to unravel the kinetics of RNA metabolism genome‐wide. Compared to the naïve state (serum), RNA synthesis and turnover rates are globally reduced in the ground state (2i) and the paused state (mTORi). The global reduction in RNA synthesis goes along with a genome‐wide decrease of polymerase elongation velocity, which is related to epigenomic features and alterations in the Pol II termination window. Our data suggest that transcription activity is the main determinant of steady state mRNA levels in the naïve state and that genome‐wide changes in transcription kinetics invoke ground and paused pluripotent states.
Caspase-Mediated Cleavage of the Transcription Factor Sp3: Possible Relevance to Cancer and the Lytic Cycle of Kaposi’s Sarcoma-Associated Herpesvirus

The ORF50 protein of Kaposi’s sarcoma-associated herpesvirus (KSHV) is the key viral protein that controls the switch from latency to lytic reactivation. It is a potent transactivator that can activate target gene promoters via interacting with other cellular DNA-binding transcription factors, such as Sp3. ABSTRACT The open reading frame 50 (ORF50) protein of Kaposi’s sarcoma-associated herpesvirus (KSHV) is the master regulator essential for initiating the viral lytic cycle. Previously, we have demonstrated that the ORF50 protein can cooperate with Sp3 to synergistically activate a set of viral and cellular gene promoters through highly conserved ORF50-responsive elements that harbor a Sp3-binding motif. Herein, we show that Sp3 undergoes proteolytic cleavage during the viral lytic cycle, and the cleavage of Sp3 is dependent on caspase activation. Since similar cleavage patterns of Sp3 could be detected in both KSHV-positive and KSHV-negative lymphoma cells undergoing apoptosis, the proteolytic cleavage of Sp3 could be a common event during apoptosis. Mutational analysis identifies 12 caspase cleavage sites in Sp3, which are situated at the aspartate (D) positions D17, D19, D180, D273, D275, D293, D304 (or D307), D326, D344, D530, D543, and D565. Importantly, we noticed that three stable Sp3 C-terminal fragments generated through cleavage at D530, D543, or D565 encompass an intact DNA-binding domain. Like the full-length Sp3, the C-terminal fragments of Sp3 could still retain the ability to cooperate with ORF50 protein to activate specific viral and cellular gene promoters synergistically. Collectively, our findings suggest that despite the proteolytic cleavage of Sp3 under apoptotic conditions, the resultant Sp3 fragments may retain biological activities important for the viral lytic cycle or for cellular apoptosis. IMPORTANCE The ORF50 protein of Kaposi’s sarcoma-associated herpesvirus (KSHV) is the key viral protein that controls the switch from latency to lytic reactivation. It is a potent transactivator that can activate target gene promoters via interacting with other cellular DNA-binding transcription factors, such as Sp3. In this report, we show that Sp3 is proteolytically cleaved during the viral lytic cycle, and up to 12 caspase cleavage sites are identified in Sp3. Despite the proteolytic cleavage of Sp3, several resulting C-terminal fragments that have intact zinc-finger DNA-binding domains still retain substantial influence in the synergy with ORF50 to activate specific gene promoters. Overall, our studies elucidate the caspase-mediated cleavage of Sp3 and uncover how ORF50 utilizes the cleavage fragments of Sp3 to transactivate specific viral and cellular gene promoters.
The effects of Silymarin on the features of cardiometabolic syndrome in adults: A systematic review and meta‐analysis

Some medicinal herbs and their effective components showed positive effects on the features of the cardiometabolic syndrome (CMS). The aim of the present systematic review and meta‐analysis is to examine the effects of silymarin on the components of CMS in adults. Four electronic databases including PubMed/Medline, Scopus, Web of Science, and Embase were systematically searched up to December 31, 2020 to identify all eligible clinical trials. A random‐effect model using DerSimonian and Laird method was used to estimate the pooled weighted mean differences (WMDs) and the 95% confidence intervals (95%CIs). Finally, 11 clinical trials met the eligibility criteria. Our results demonstrated that silymarin significantly reduced the levels of fasting blood glucose (WMD: −17.96 mg/dL, 95% CI: −32.91, −3.02;I2: 82.4%, p < 0.001), hemoglobin A1C (WMD: −1.25%, 95% CI: −2.34, 0.16; I2: 92.9%, p ˂ 0.001), total cholesterol (WMD: −17.46 mg/dL, 95% CI: −30.98, −3.95; I2 = 62.9%, p = 0.006), triglyceride (WMD: −25.70 mg/dL, 95% CI: −47.23, −4.17; I2:54.3%, p = 0.025), low‐density lipoprotein‐cholesterol (WMD: ‐10.53, 95% CI: −19.12, −1.94; I2: 37.5%, p = 0.119) and increased high‐density lipoprotein‐ cholesterol (WMD: 3.36 mg/dL, 95% CI: 0.88, 5.84; I2: 37.4%, p = 0.120) compared to placebo. However, its effects on BMI were not statistically significant. Silymarin can be an effective complementary therapy to improve most features of CMS. However, due to high heterogeneity and limited clinical trials in some parameters, further high‐quality clinical trials are needed to confirm its efficacy.
Crry silencing alleviates Alzheimer’s disease injury by regulating neuroinflammatory cytokines and the complement system

Complement component (3b/4b) receptor 1 (CR1) expression is positively related to the abundance of phosphorylated microtubule-associated protein tau (tau), and CR1 expression is associated with susceptibility to Alzheimer’s disease. However, the exact role of CR1 in tau protein-associated neurodegenerative diseases is unknown. In this study, we show that the mouse Cr1-related protein Y (Crry) gene, Crry, is localized to microglia. We also found that Crry protein expression in the hippocampus and cortex was significantly elevated in P301S mice (a mouse model widely used for investigating tau pathology) compared with that in wild-type mice. Tau protein phosphorylation (at serine 202, threonine 205, threonine 231, and serine 262) and expression of the major tau kinases glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 were greater in P301S mice than in wild-type mice. Crry silencing by lentivirus-transfected short hairpin RNA led to greatly reduced tau phosphorylation and glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 activity. Crry silencing reduced neuronal apoptosis and rescued cognitive impairment of P301S mice. Crry silencing also reduced the levels of the neuroinflammatory factors interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 and the complement components complement 3 and complement component 3b. Our results suggest that Crry silencing in the P301S mouse model reduces tau protein phosphorylation by reducing the levels of neuroinflammation and complement components, thereby improving cognitive function.