Miracle-dz/UniFAR-FTUs huggingface dataset:
Repetitive Transcranial Magnetic Stimulation on Motor Recovery for Patients With Stroke

Supplemental digital content is available in the text. Objective A systematic review and meta-analysis were conducted to determine the efficacy of repetitive transcranial magnetic stimulation in recovering motor function in patients with stroke. Design A comprehensive literature search was performed to identify studies published before September 20, 2018. Electronic databases were searched. Standard mean differences and 95% confidence intervals were used to evaluate the effects of repetitive transcranial magnetic stimulation. The stability and sensitivity of the results and sources of heterogeneity were also analyzed. The Cochrane Risk of Bias Tool was used to determine the quality of the studies. Result Twenty randomized controlled trials (N = 841 patients) were included. The results showed that repetitive transcranial magnetic stimulation is beneficial to patients with poststroke hemiplegia, as demonstrated by the following four scales: the Fugl-Meyer Assessment (standard mean difference = 0.635, 95% confidence interval = 0.421 to 0.848); grip strength (standard mean difference = 1.147, 95% confidence interval = 0.761 to 1.534); Barthel Index (Standard mean difference = 0.580, 95% confidence interval = 0.377 to 0.783); and National Institutes of Health Stroke Scale (standard mean difference = −0.555, 95% confidence interval = −0.813 to −0.298). Few adverse events were observed. Conclusions The analysis showed that low-frequency repetitive transcranial magnetic stimulation has a positive effect on grip strength and lower limb function as assessed by FMA.
Mucoadhesive Electrospun Patch Delivery of Lidocaine to the Oral Mucosa and Investigation of Spatial Distribution in a Tissue Using MALDI-Mass Spectrometry Imaging

Many oral mucosal conditions cause considerable and prolonged pain that to date has been difficult to alleviate via topical delivery, and the use of injection causes many patients dental anxiety and needle-prick pain. Therefore, developing a noninjectable drug delivery system as an alternative administration procedure may vastly improve the health and wellbeing of these patients. Recent advances in the development of mucoadhesive electrospun patches for the direct delivery of therapeutics to the oral mucosa offer a potential solution, but as yet, the release of local anesthetics from this system and their uptake by oral tissue have not been demonstrated. Here, we demonstrate the fabrication of lidocaine-loaded electrospun fiber patches, drug release, and subsequent uptake and permeation through the porcine buccal mucosa. Lidocaine HCl and lidocaine base were incorporated into the electrospun patches to evaluate the difference in drug permeation for the two drug compositions. Lidocaine released from the lidocaine HCl-containing electrospun patches was significantly quicker than from the lidocaine base patches, with double the amount of drug released from the lidocaine HCl patches in the first 15 min (0.16 ± 0.04 mg) compared to that from the lidocaine base patches (0.07 ± 0.01 mg). The permeation of lidocaine from the lidocaine HCl electrospun patches through ex vivo porcine buccal mucosa was also detected in 15 min, whereas permeation of lidocaine from the lidocaine base patch was not detected. Matrix-assisted laser desorption ionization-mass spectrometry imaging was used to investigate localization of lidocaine within the oral tissue. Lidocaine in the solution as well as from the mucoadhesive patch penetrated into the buccal mucosal tissue in a time-dependent manner and was detectable in the lamina propria after only 15 min. Moreover, the lidocaine released from lidocaine HCl electrospun patches retained biological activity, inhibiting veratridine-mediated opening of voltage-gated sodium channels in SH-SY5Y neuroblastoma cells. These data suggest that a mucoadhesive electrospun patch may be used as a vehicle for rapid uptake and sustained anesthetic drug delivery to treat or prevent oral pain.
Deletion of the transmembrane protein Prom1b in zebrafish disrupts outer-segment morphogenesis and causes photoreceptor degeneration

Mutations in human prominin 1 (PROM1), encoding a transmembrane glycoprotein localized mainly to plasma membrane protrusions, have been reported to cause retinitis pigmentosa, macular degeneration, and cone–rod dystrophy. Although the structural role of PROM1 in outer-segment (OS) morphogenesis has been demonstrated in Prom1-knockout mouse, the mechanisms underlying these complex disease phenotypes remain unclear. Here, we utilized a zebrafish model to further investigate PROM1's role in the retina. The Prom1 orthologs in zebrafish include prom1a and prom1b, and our results showed that prom1b, rather than prom1a, plays an important role in zebrafish photoreceptors. Loss of prom1b disrupted OS morphogenesis, with rods and cones exhibiting differences in impairment: cones degenerated at an early age, whereas rods remained viable but with an abnormal OS, even at 9 months postfertilization. Immunofluorescence experiments with WT zebrafish revealed that Prph2, an ortholog of the human transmembrane protein peripherin 2 and also associated with OS formation, is localized to the edge of OS and is more highly expressed in the cone OS than in the rod OS. Moreover, we found that Prom1b deletion causes mislocalization of Prph2 and disrupts its oligomerization. We conclude that the variation in Prph2 levels between cones and rods was one of the reasons for the different PROM1 mutation–induced phenotypes of these retinal structures. These findings expand our understanding of the phenotypes caused by PROM1 mutations and provide critical insights into its function.
Pharmacological Interventions and Rehabilitation Approach for Enhancing Brain Self-repair and Stroke Recovery

Neuroplasticity is a natural process occurring in the brain for the entire life. Stroke is the leading cause of long term disability and a huge medical and financial problem throughout the world. Research conducted over the past decade focused mainly on neuroprotection in the acute phase of stroke while very little studies target the chronic stage. Recovery after stroke depends on the ability of our brain to reestablish the structural and functional organization of neurovascular networks. Combining adjuvant therapies and drugs may enhance the repair processes and restore impaired brain functions. Currently, there are some drugs and rehabilitative strategies that can facilitate brain repair and improve clinical effect even years after stroke onset. Moreover, some of the compounds such as citicoline, fluoxetine, niacin, levodopa, etc. are already in clinical use or are being trialed in clinical issues. Many studies are also testing cell therapies; in our review, we focused on studies where cells have been implemented at the early stage of stroke. Next, we discuss pharmaceutical interventions. In this section, we selected methods of cognitive, behavioral, and physical rehabilitation as well as adjuvant interventions for neuroprotection including noninvasive brain stimulation and extremely low-frequency electromagnetic field. The modern rehabilitation represents a new model of physical interventions with the limited therapeutic window up to six months after stroke. However, previous studies suggest that the time window for stroke recovery is much longer than previously thought. This review attempts to present the progress in neuroprotective strategies, both pharmacological and non-pharmacological that can stimulate the endogenous neuroplasticity in post-stroke patients.
FICC-Seq: a method for enzyme-specified profiling of methyl-5-uridine in cellular RNA

Abstract Methyl-5-uridine (m5U) is one the most abundant non-canonical bases present in cellular RNA, and in yeast is found at position U54 of tRNAs where modification is catalysed by the methyltransferase Trm2. Although the mammalian enzymes that catalyse m5U formation are yet to be identified via experimental evidence, based on sequence homology to Trm2, two candidates currently exist, TRMT2A and TRMT2B. Here we developed a genome-wide single-nucleotide resolution mapping method, Fluorouracil-Induced-Catalytic-Crosslinking-Sequencing (FICC-Seq), in order to identify the relevant enzymatic targets. We demonstrate that TRMT2A is responsible for the majority of m5U present in human RNA, and that it commonly targets U54 of cytosolic tRNAs. By comparison to current methods, we show that FICC-Seq is a particularly robust method for accurate and reliable detection of relevant enzymatic target sites. Our associated finding of extensive irreversible TRMT2A-tRNA crosslinking in vivo following 5-Fluorouracil exposure is also intriguing, as it suggests a tangible mechanism for a previously suspected RNA-dependent route of Fluorouracil-mediated cytotoxicity.
Venous thromboembolism prophylaxis in thoracic surgery patients: an international survey.

OBJECTIVES Venous thromboembolic events (VTE) after thoracic surgery (TS) can be prevented with mechanical and chemical prophylaxis. Unlike other surgical specialties, TS lacks evidence-based guidelines. In the process of developing these guidelines, an understanding of the current prophylaxis methods practiced internationally is necessary and is described in this article. METHODS A 26-item survey was distributed to members of the European Society of Thoracic Surgeons (ESTS), American Association of Thoracic Surgery (AATS), Japanese Association for Chest Surgery (JACS) and Chinese Society for Thoracic and Cardiovascular Surgery (CSTCS) electronically or in person. Participants were asked to report their current prophylaxis selection, timing of initiation and duration of prophylaxis, perceived risk factors and the presence and adherence to institutional VTE guidelines for patients undergoing TS for malignancies. RESULTS In total, 1613 surgeons anonymously completed the survey with an overall 36% response rate. Respondents were senior surgeons working in large academic hospitals (≥70%, respectively). More than 83.5% of ESTS, AATS and JACS respondents report formal TS thromboprophylaxis protocols in their institutions, but 53% of CSTCS members report not having such a protocol. The regions varied in the approaches utilized for VTE prophylaxis, the timing of initiation perioperatively and the use and type of extended prophylaxis. Respondents reported that multiple risk factors and sources of information impact their VTE prophylaxis decision-making processes, and these factors vastly diverge regionally. CONCLUSIONS There is little agreement internationally on the optimal approach to thromboprophylaxis in the TS population, and guidelines will be helpful and vastly welcomed.
'Ghost introgression' as a cause of deep mitochondrial divergence in a bird species complex.

In the absence of nuclear-genomic differentiation between two populations, deep mitochondrial divergence (DMD) is a form of mito-nuclear discordance. Such instances of DMD are rare and might variably be explained by unusual cases of female-linked selection, by male-biased dispersal, by 'speciation reversal' or by mitochondrial capture through genetic introgression. Here we analyze DMD in an Asian Phylloscopus leaf warbler (Aves: Phylloscopidae) complex. Bioacoustic, morphological and genomic data demonstrate close similarity between the taxa affinis and occisinensis, even though DMD previously led to their classification as two distinct species. Using population genomic and comparative genomic methods on 45 whole genomes, including historical reconstructions of effective population size, genomic peaks of differentiation and genomic linkage, we infer that the form affinis is likely the product of a westward expansion in which it replaced a now-extinct congener that was the donor of its mtDNA and small portions of its nuclear genome. This study provides strong evidence of 'ghost introgression' as the cause of DMD, and we suggest that 'ghost introgression' may be a widely overlooked phenomenon in nature.
NADPH oxidase regulates chemotropic growth of the fungal pathogen Fusarium oxysporum towards the host plant.

Soil-inhabiting fungal pathogens use chemical signals to locate and colonize the host plant. In the vascular wilt fungus Fusarium oxysporum, hyphal chemotropism towards tomato roots is triggered by secreted plant peroxidases (Prx), which catalyze the reductive cleavage of reactive oxygen species (ROS). Here we show that this chemotropic response requires the regulated synthesis of ROS by the conserved fungal NADPH oxidase B (NoxB) complex, and their transformation into hydrogen peroxide (H2 O2 ) by superoxide dismutase (SOD). Deletion of NoxB or the regulatory subunit NoxR, or pharmacological inhibition of SOD, specifically abolished chemotropism of F. oxysporum towards Prx gradients. Addition of isotropic concentrations of H2 O2 rescued chemotropic growth in the noxBΔ and noxRΔ mutants, but not in a mutant lacking the G protein coupled receptor Ste2. Prx triggered rapid Nox- and Ste2-dependent phosphorylation of the cell wall integrity mitogen-activated protein kinase (CWI MAPK) Mpk1, an essential component of the chemotropic response. These results suggest that Ste2 and the CWI MAPK cascade function downstream of NoxB in Prx chemosensing. Our findings reveal a new role for Nox enzymes in directed hyphal growth of a filamentous pathogen towards its host and might be of broad interest for chemotropic interactions between plants and root-colonizing fungi. This article is protected by copyright. All rights reserved.
Does Beta Amyloid Immunization Reduce Amyloid Plaques and Preserve Cognitive Function in Patients with Alzheimer's Disease?

Objective The objective of this systematic review is to examine the efficacy of beta amyloid immunization in reducing amyloid plaques and preserving cognitive function in patients with Alzheimer’s disease (AD). Study Design Review of three English language randomized, placebo-controlled, double-blind clinical trials from 2005-2009. Data Sources Randomized, placebo-controlled, double-blind clinical trials comparing active immunization with aggregated human β-amyloid AN1792 and QS-21 (an adjuvant) to placebo were found using the Cochrane Database of Randomized Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE. Outcome(s) Measured Cognitive function compared to baseline as measured using three cognitive tests: the Alzheimer’s Disease Assessment Scale Cognitive Sub-scale (ADAS-Cog), which is measured on a scale from 0-70 in which a higher score indicates greater impairment; the Folstein Mini-Mental State Examination (MMSE), which is measured on a scale from 0-30 and in which a lower score indicates greater impairment; and a Neuropsychological Test Battery (NTB) that consisted of nine components with varying scores. Results The Bayer trial (phase Ib) showed a positive antibody response to AN1792, but the ADAS-Cogs scores increased and MMSE scores decreased in both the active and control groups during the study, indicating a decline in cognition. The Bayer trial did not utilize the NTB. The Gilman trial (phase IIa) showed no significant difference in cognitive function between the active and control groups using the ADAS-Cog and MMSE, but the NTB showed cognitive improvement compared with the placebo group and a small improvement from baseline when measured at month 12. However, the Gilman trial ended prematurely after 6% of the patients (18/300) developed aseptic meningoencephalitis. The cohort study of the phase IIa trial (Vellas) was conducted 4.6 years after immunization with AN1792, and showed no significant change from baseline or differences between antibody responders and placebo group using the ADAS-Cog, MMSE, and NTB scores. Conclusions This therapy does not appear to maintain nor enhance long-term cognitive function in patients with AD.
Cephalosporins: A Focus on Side Chains and β-Lactam Cross-Reactivity

Cephalosporins are among the most commonly prescribed antibiotic classes due to their wide clinical utility and general tolerability, with approximately 1–3% of the population reporting a cephalosporin allergy. However, clinicians may avoid the use of cephalosporins in patients with reported penicillin allergies despite the low potential for cross-reactivity. The misdiagnosis of β-lactam allergies and misunderstanding of cross-reactivity among β-lactams, including within the cephalosporin class, often leads to use of broader spectrum antibiotics with poor safety and efficacy profiles and represents a serious obstacle for antimicrobial stewardship. Risk factors for cephalosporin allergies are broad and include female sex, advanced age, and a history of another antibiotic or penicillin allergy; however, cephalosporins are readily tolerated even among individuals with true immediate-type allergies to penicillins. Cephalosporin cross-reactivity potential is related to the structural R1 side chain, and clinicians should be cognizant of R1 side chain similarities when prescribing alternate β-lactams in allergic individuals or when new cephalosporins are brought to market. Clinicians should consider the low likelihood of true cephalosporin allergy when clinically indicated. The purpose of this review is to provide an overview of the role of cephalosporins in clinical practice, and to highlight the incidence of, risk factors for, and cross-reactivity of cephalosporins with other antibiotics.
Polymorphic G:G mismatches act as hotspots for inducing right-handed Z DNA by DNA intercalation

Abstract DNA mismatches are highly polymorphic and dynamic in nature, albeit poorly characterized structurally. We utilized the antitumour antibiotic CoII(Chro)2 (Chro = chromomycin A3) to stabilize the palindromic duplex d(TTGGCGAA) DNA with two G:G mismatches, allowing X-ray crystallography-based monitoring of mismatch polymorphism. For the first time, the unusual geometry of several G:G mismatches including syn–syn, water mediated anti–syn and syn–syn-like conformations can be simultaneously observed in the crystal structure. The G:G mismatch sites of the d(TTGGCGAA) duplex can also act as a hotspot for the formation of alternative DNA structures with a GC/GA-5′ intercalation site for binding by the GC-selective intercalator actinomycin D (ActiD). Direct intercalation of two ActiD molecules to G:G mismatch sites causes DNA rearrangements, resulting in backbone distortion to form right-handed Z-DNA structures with a single-step sharp kink. Our study provides insights on intercalators-mismatch DNA interactions and a rationale for mismatch interrogation and detection via DNA intercalation.
Prevalence of Maternal‐Risk Factors Related to Neonatal Abstinence Syndrome in a Commercial Claims Database: 2011‐2015

Despite the rising incidence of neonatal abstinence syndrome (NAS), data evaluating trends in maternal risk factors associated with NAS have not been available for recent years, a period characterized by declining opioid prescriptions. The objective of this study was to examine the prevalence of opioid‐ and non–opioid‐related factors associated with NAS, and by mutually exclusive subgroups of deliveries without prescription‐opioid use, with prescription‐opioid use, and with opioid‐use disorder (OUD).
Staufen1 and UPF1 exert opposite actions on the replacement of the nuclear cap-binding complex by eIF4E at the 5′ end of mRNAs

Abstract Newly synthesized mRNAs are exported from the nucleus to cytoplasm with a 5′-cap structure bound by the nuclear cap-binding complex (CBC). During or after export, the CBC should be properly replaced by cytoplasmic cap-binding protein eIF4E for efficient protein synthesis. Nonetheless, little is known about how the replacement takes place. Here, we show that double-stranded RNA-binding protein staufen1 (STAU1) promotes efficient replacement by facilitating an association between the CBC–importin α complex and importin β. Our transcriptome-wide analyses and artificial tethering experiments also reveal that the replacement occurs more efficiently when an mRNA associates with STAU1. This event is inhibited by a key nonsense-mediated mRNA decay factor, UPF1, which directly interacts with STAU1. Furthermore, we find that cellular apoptosis that is induced by ionizing radiation is accompanied by inhibition of the replacement via increased association between STAU1 and hyperphosphorylated UPF1. Altogether, our data highlight the functional importance of STAU1 and UPF1 in the course of the replacement of the CBC by eIF4E, adding a previously unappreciated layer of post-transcriptional gene regulation.
Correlation of IL-33 gene polymorphism with chronic obstructive pulmonary disease.

OBJECTIVE To explore the correlation between interleukin (IL)-33 gene polymorphism with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS A total of 210 COPD patients (observation group) and 180 healthy people receiving physical examinations (control group) were included in this study. Clinical information of each subject was collected. Relative levels of inflammation-related factor IL-33 and pulmonary function indexes were determined. Moreover, the polymorphism of IL-33 rs1891385 was detected with the TaqMan-minor groove binder (MGB) probe. RESULTS Observation group had a higher level of IL-33 than that of control group (p<0.01), and the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio (%) and FEV1/the predicted value ratio (%) in observation group were lower than those in control group (p<0.05). There were significant differences in the distribution frequencies of genotypes and alleles between the two groups (p<0.05), and genotype AA exhibited a higher level of IL-33, but a lower FEV1/FVC ratio (%) and FEV1/the predicted value ratio (%) than those of genotypes AC and CC (p<0.05). CONCLUSIONS IL-33 and pulmonary function test can be used to effectively evaluate the progression of COPD, and the polymorphism of IL-33 rs1891385 is correlated with the onset of COPD.
Carbon isotopic heterogeneity of coenzyme F430 and membrane lipids in methane‐oxidizing archaea

Archaeal ANaerobic MEthanotrophs (ANME) facilitate the anaerobic oxidation of methane (AOM), a process that is believed to proceed via the reversal of the methanogenesis pathway. Carbon isotopic composition studies indicate that ANME are metabolically diverse and able to assimilate metabolites including methane, methanol, acetate, and dissolved inorganic carbon (DIC). Our data support the interpretation that ANME in marine sediments at methane seeps assimilate both methane and DIC, and the carbon isotopic compositions of the tetrapyrrole coenzyme F430 and the membrane lipids archaeol and hydroxy‐archaeol reflect their relative proportions of carbon from these substrates. Methane is assimilated via the methyl group of CH3‐tetrahydromethanopterin (H4MPT) and DIC from carboxylation reactions that incorporate free intracellular DIC. F430 was enriched in 13C (mean δ13C = −27‰ for Hydrate Ridge and −80‰ for the Santa Monica Basin) compared to the archaeal lipids (mean δ13C = −97‰ for Hydrate Ridge and −122‰ for the Santa Monica Basin). We propose that depending on the side of the tricarboxylic acid (TCA) cycle used to synthesize F430, its carbon was derived from 76% DIC and 24% methane via the reductive side or 57% DIC and 43% methane via the oxidative side. ANME lipids are predicted to contain 42% DIC and 58% methane, reflecting the amount of each assimilated into acetyl‐CoA. With isotope models that include variable fractionation during biosynthesis for different carbon substrates, we show the estimated amounts of DIC and methane can result in carbon isotopic compositions of − 73‰ to − 77‰ for F430 and − 105‰ for archaeal lipids, values close to those for Santa Monica Basin. The F430 δ13C value for Hydrate Ridge was 13C‐enriched compared with the modeled value, suggesting there is divergence from the predicted two carbon source models.