Miracle-dz/UniFAR-FTUs huggingface dataset:
How Is Precursor Messenger RNA Spliced by the Spliceosome?

Splicing of the precursor messenger RNA, involving intron removal and exon ligation, is mediated by the spliceosome. Together with biochemical and genetic investigations of the past four decades, structural studies of the intact spliceosome at atomic resolution since 2015 have led to mechanistic delineation of RNA splicing with remarkable insights. The spliceosome is proven to be a protein-orchestrated metalloribozyme. Conserved elements of small nuclear RNA (snRNA) constitute the splicing active site with two catalytic metal ions and recognize three conserved intron elements through duplex formation, which are delivered into the splicing active site for branching and exon ligation. The protein components of the spliceosome stabilize the conformation of the snRNA, drive spliceosome remodeling, orchestrate the movement of the RNA elements, and facilitate the splicing reaction. The overall organization of the spliceosome and the configuration of the splicing active site are strictly conserved between human and yeast. Expected final online publication date for the Annual Review of Biochemistry, Volume 89 is June 22, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Peptide-based therapy in portal hypertension.

PURPOSE OF REVIEW To summarize the use of gastrointestinal peptides in the management of portal hypertension. RECENT FINDINGS Vasoactive peptides are commonly used in the management of acute variceal hemorrhage and hepatorenal syndrome, which are portal hypertensive complications of cirrhosis. The main vasoactive peptides that are used are somatostatin and its long-acting analogue octreotide, and vasopressin and its analogue terlipressin. Early initiation of vasoactive peptides in the management of acute variceal hemorrhage and hepatorenal syndrome is associated with improved outcomes. Octreotide is the available vasoactive peptide in the Unites States. Recent developments and ongoing clinical trials may improve our understanding of hepatorenal syndrome and influence the use of vasoactive peptides, particularly terlipressin. SUMMARY Here, we review the literature on the use of vasoactive peptides in the management of acute variceal hemorrhage and hepatorenal syndrome.
Characterization and Application of PVDF and Its Copolymer Films Prepared by Spin-Coating and Langmuir–Blodgett Method

Poly(vinylidene fluoride) (PVDF) and its copolymers are key polymers, displaying properties such as flexibility and electroactive responses, including piezoelectricity, pyroelectricity, and ferroelectricity. In the past several years, they have been applied in numerous applications, such as memory, transducers, actuators, and energy harvesting and have shown thriving prospects in the ongoing research and commercialization process. The crystalline polymorphs of PVDF can present nonpolar α, ε phase and polar β, γ, and δ phases with different processing methods. The copolymers, such as poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)), can crystallize directly into a phase analogous to the β phase of PVDF. Since the β phase shows the highest dipole moment among polar phases, many reproducible and efficient methods producing β-phase PVDF and its copolymer have been proposed. In this review, PVDF and its copolymer films prepared by spin-coating and Langmuir–Blodgett (LB) method are introduced, and relevant characterization techniques are highlighted. Finally, the development of memory, artificial synapses, and medical applications based on PVDF and its copolymers is elaborated.
Multidiameter single-fiber reflectance spectroscopy of heavily pigmented skin: modeling the inhomogeneous distribution of melanin

Abstract. When analyzing multidiameter single-fiber reflectance (MDSFR) spectra, the inhomogeneous distribution of melanin pigments in skin tissue is usually not accounted for. Especially in heavily pigmented skins, this can result in bad fits and biased estimation of tissue optical properties. A model is introduced to account for the inhomogeneous distribution of melanin pigments in skin tissue. In vivo visible MDSFR measurements were performed on heavily pigmented skin of type IV to VI. Skin tissue optical properties and related physiological properties were extracted from the measured spectra using the introduced model. The absorption of melanin pigments described by the introduced model demonstrates a good correlation with the co-localized measurement of the well-known melanin index.
Physical stability of dry powder inhaler formulations

ABSTRACT Introduction: Dry powder inhalers (DPIs) are popular for pulmonary drug delivery. Various techniques have been employed to produce inhalation drug particles and improve the delivery efficiency of DPI formulations. Physical stability of these DPI formulations is critical to ensure the delivery of a reproducible dose to the airways over the shelf-life. Areas covered: This review focuses on the impact of solid-state stability on aerosolization performance of DPI drug particles manufactured by powder production approaches and particle-engineering techniques. It also highlights the different analytical tools that can be used to characterize the physical instability originating from production and storage. Expert opinion: A majority of the DPI literature focuses on the effects of physico-chemical properties such as size, morphology, and density on aerosolization. While little has been reported on the physical stability, particularly the stability of engineered drug particles for use in DPIs. Literature data have shown that different particle-engineering methods and storage conditions may cause physical instability of dry powders for inhalation and can significantly change the aerosol performance. A systematic examination of physical instability mechanisms in DPI formulations is necessary during formulation development in order to select the optimum formulation with satisfactory stability. In addition, the use of appropriate characterization tools is critical to detect and understand physical instability during the development of DPI formulations.
Recombinant Modified Vaccinia Virus Ankara (MVA) Vaccines Efficiently Protect Cockatiels Against Parrot Bornavirus Infection and Proventricular Dilatation Disease

Parrot bornaviruses (PaBVs) are the causative agents of proventricular dilatation disease (PDD), a chronic and often fatal neurologic disorder in Psittaciformes. The disease is widely distributed in private parrot collections and threatens breeding populations of endangered species. Thus, immunoprophylaxis strategies are urgently needed. In previous studies we demonstrated a prime-boost vaccination regime using modified vaccinia virus Ankara (MVA) and Newcastle disease virus (NDV) constructs expressing the nucleoprotein and phosphoprotein of PaBV-4 (MVA/PaBV-4 and NDV/PaBV-4, respectively) to protect cockatiels (Nymphicus hollandicus) against experimental challenge infection. Here we investigated the protective effect provided by repeated immunization with either MVA/PaBV-4, NDV/PaBV-4 or Orf virus constructs (ORFV/PaBV-4) individually. While MVA/PaBV-4-vaccinated cockatiels were completely protected against subsequent PaBV-2 challenge infection and PDD-associated lesions, the course of the challenge infection in NDV/PaBV-4- or ORFV/PaBV-4-vaccinated birds did not differ from the unvaccinated control group. We further investigated the effect of vaccination on persistently PaBV-4-infected cockatiels. Remarkably, subsequent immunization with MVA/PaBV-4 and NDV/PaBV-4 neither induced obvious immunopathogenesis exacerbating the disease nor reduced viral loads in the infected birds. In summary, we demonstrated that vaccination with MVA/PaBV-4 alone is sufficient to efficiently prevent PaBV-2 challenge infection in cockatiels, providing a suitable vaccine candidate against avian bornavirus infection and bornavirus-induced PDD.
Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection

BACKGROUND Respiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T cells play a key role in antiviral immunity, but they have been little studied in the human lung. METHODS Healthy adult volunteers were inoculated i.n. with RSV A Memphis 37. CD4+ T cells in blood and the lower airway were analyzed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding. RESULTS Activated CD4+ T cell frequencies in bronchoalveolar lavage correlated strongly with local C-X-C motif chemokine 10 levels. Thirty-nine epitopes were identified, predominantly toward the 3′ end of the viral genome. Five novel MHC II tetramers were made using an immunodominant EFYQSTCSAVSKGYL (F-EFY) epitope restricted to HLA-DR4, -DR9, and -DR11 (combined allelic frequency: 15% in Europeans) and G-DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labeling revealed enrichment of resident memory CD4+ T (Trm) cells in the lower airway; these Trm cells displayed progressive differentiation, downregulation of costimulatory molecules, and elevated CXCR3 expression as infection evolved. CONCLUSIONS Human infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of Trm recognizing novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines. TRIAL REGISTRATION ClinicalTrials.gov NCT02755948. FUNDING Medical Research Council, Wellcome Trust, National Institute for Health Research.
Extracellular electron transfer powers flavinylated extracellular reductases in Gram-positive bacteria

Significance Strategies of energy metabolism are variable across the microbial world and fundamentally reflect distinct ecological dynamics. The complex electron transfer mechanisms that support many such processes take place in the cell membrane but can be wired to the exterior of the cell in some circumstances. The results presented here reveal a family of extracellular reductases that possess a post-translationally flavinylated sequence motif. This motif provides a conserved framework that mediates electron transfer from the membrane to different extracellular small molecules. These findings advance our understanding of microbial energy metabolism and identify a generalized and modular electron transfer strategy that could be exploited for applications in metabolic engineering. Mineral-respiring bacteria use a process called extracellular electron transfer to route their respiratory electron transport chain to insoluble electron acceptors on the exterior of the cell. We recently characterized a flavin-based extracellular electron transfer system that is present in the foodborne pathogen Listeria monocytogenes, as well as many other Gram-positive bacteria, and which highlights a more generalized role for extracellular electron transfer in microbial metabolism. Here we identify a family of putative extracellular reductases that possess a conserved posttranslational flavinylation modification. Phylogenetic analyses suggest that divergent flavinylated extracellular reductase subfamilies possess distinct and often unidentified substrate specificities. We show that flavinylation of a member of the fumarate reductase subfamily allows this enzyme to receive electrons from the extracellular electron transfer system and support L. monocytogenes growth. We demonstrate that this represents a generalizable mechanism by finding that a L. monocytogenes strain engineered to express a flavinylated extracellular urocanate reductase uses urocanate by a related mechanism and to a similar effect. These studies thus identify an enzyme family that exploits a modular flavin-based electron transfer strategy to reduce distinct extracellular substrates and support a multifunctional view of the role of extracellular electron transfer activities in microbial physiology.
Attention Networks in the Parietooccipital Cortex Modulate Activity of the Human Vestibular Cortex during Attentive Visual Processing

Previous studies in human subjects reported that the parieto-insular vestibular cortex (PIVC), a core area of the vestibular cortex, is inhibited when visual processing is prioritized. However, it has remained unclear which networks in the brain modulate this inhibition of PIVC. Based on previous results showing that the inhibition of PIVC is strongly influenced by visual attention, we here examined whether attention networks in the parietooccipital cortex modulate the inhibition of PIVC. Using diffusion-weighted and resting-state fMRI in a group of female and male subjects, we found structural and functional connections between PIVC and the posterior parietal cortex (PPC), a major brain region of the cortical attention network. We then temporarily inhibited PPC by repetitive transcranial magnetic stimulation (rTMS) and hypothesized that the modulatory influence of PPC over PIVC would be reduced; and, as a result, PIVC would be less inhibited. Subjects performed a visual attentional tracking task immediately after rTMS, and the inhibition of PIVC during attentive tracking was measured with fMRI. The results showed that the inhibition of PIVC during attentive tracking was less pronounced compared with sham rTMS. We also examined the effects of inhibitory rTMS over the occipital cortex and found that the visual-vestibular posterior insular cortex area was less activated during attentive tracking compared with sham rTMS or rTMS over PPC. Together, these results suggest that attention networks in the parietooccipital cortex modulate activity in core areas of the vestibular cortex during attentive visual processing. SIGNIFICANCE STATEMENT Although multisensory integration is generally considered beneficial, it can become detrimental when cues from different senses are in conflict. The occurrence of such multisensory conflicts can be minimized by inhibiting core cortical areas of the subordinate sensory system (e.g., vestibular), thus reducing potential conflict with ongoing processing of the prevailing sensory (e.g., visual) cues. However, it has remained unclear which networks in the brain modulate the magnitude of inhibition of the subordinate sensory system. Here, by investigating the inhibition of the vestibular sensory system when visual processing is prioritized, we show that attention networks in the parietooccipital cortex modulate the magnitude of inhibition of the vestibular cortex.
Dissecting the Antimicrobial Composition of Honey

Honey is a complex sweet food stuff with well-established antimicrobial and antioxidant properties. It has been used for millennia in a variety of applications, but the most noteworthy include the treatment of surface wounds, burns and inflammation. A variety of substances in honey have been suggested as the key component to its antimicrobial potential; polyphenolic compounds, hydrogen peroxide, methylglyoxal and bee-defensin 1. These components vary greatly across honey samples due to botanical origin, geographical location and secretions from the bee. The use of medical grade honey in the treatment of surface wounds and burns has been seen to improve the healing process, reduce healing time, reduce scarring and prevent microbial contamination. Therefore, if medical grade honeys were to be included in clinical treatment, it would reduce the demand for antibiotic usage. In this review, we outline the constituents of honey and how they affect antibiotic potential in a clinical setting. By identifying the key components, we facilitate the development of an optimally antimicrobial honey by either synthetic or semisynthetic production methods.
Efficacy of empagliflozin on heart failure and renal outcomes in patients with atrial fibrillation: data from the EMPA‐REG OUTCOME trial

Atrial fibrillation (AF) is common in patients with diabetes and heart failure (HF) and increases the future risk of adverse cardiovascular (CV) outcomes. This analysis from the EMPA‐REG OUTCOME trial explores CV and renal outcomes in patients with vs. without AF at baseline and assesses the benefits of empagliflozin.
Predicting 6-Month Mortality for Older Adults Hospitalized With Acute Myocardial Infarction

Background Older adults with acute myocardial infarction (AMI) have higher prevalence of functional impairments, including deficits in cognition, strength, and sensory domains, than their younger counterparts. Objective To develop and evaluate the prognostic utility of a risk model for 6-month post-AMI mortality in older adults that incorporates information about functional impairments. Design Prospective cohort study. (ClinicalTrials.gov: NCT01755052). Setting 94 hospitals throughout the United States. Participants 3006 persons aged 75 years or older who were hospitalized with AMI and discharged alive. Measurements Functional impairments were assessed during hospitalization via direct measurement (cognition, mobility, muscle strength) or self-report (vision, hearing). Clinical variables associated with mortality in prior risk models were ascertained by chart review. Seventy-two candidate variables were selected for inclusion, and backward selection and Bayesian model averaging were used to derive (n = 2004 participants) and validate (n = 1002 participants) a model for 6-month mortality. Results Participants' mean age was 81.5 years, 44.4% were women, and 10.5% were nonwhite. There were 266 deaths (8.8%) within 6 months. The final risk model included 15 variables, 4 of which were not included in prior risk models: hearing impairment, mobility impairment, weight loss, and lower patient-reported health status. The model was well calibrated (Hosmer-Lemeshow P > 0.05) and showed good discrimination (area under the curve for the validation cohort = 0.84). Adding functional impairments significantly improved model performance, as evidenced by category-free net reclassification improvement indices of 0.21 (P = 0.008) for hearing impairment and 0.26 (P < 0.001) for mobility impairment. Limitation The model was not externally validated. Conclusion A newly developed model for 6-month post-AMI mortality in older adults was well calibrated and had good discriminatory ability. This model may be useful in decision making at hospital discharge. Primary Funding Source National Heart, Lung, and Blood Institute of the National Institutes of Health.
Cytomorphologic features of small cell carcinoma of lung in effusion fluid using a liquid‐based cytology technique

Liquid‐based cytology (LBC) testing induces morphologic changes due to the use of specific fixatives and preparation techniques, and the cytologies of effusions determined in this manner differ morphologically from those of conventional cytopreparation (CCP) smear methods. We compared the cytologic features of pulmonary small cell carcinoma in effusion fluid using CCP and LBC preparations.
Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion

Testosterone is a driver of prostate cancer (PC) growth via ligand‐mediated activation of the androgen receptor (AR). Tumors that have escaped systemic androgen deprivation, castration‐resistant prostate cancers (CRPC), have measurable intratumoral levels of testosterone, suggesting that a resistance mechanism still depends on androgen‐simulated growth. However, AR activation requires an optimal intracellular concentration of androgens, a situation challenged by low circulating testosterone concentrations. Notably, PC cells may optimize their androgen levels by regulating the expression of steroid metabolism enzymes that convert androgen precursors into androgens. Here we propose that testosterone entry into the cell could be another control point.
Human Genomic Diversity Where the Mediterranean Joins the Atlantic

Abstract Throughout the past few years, a lively debate emerged about the timing and magnitude of the human migrations between the Iberian Peninsula and the Maghreb. Several pieces of evidence, including archaeological, anthropological, historical, and genetic data, have pointed to a complex and intermingled evolutionary history in the western Mediterranean area. To study to what extent connections across the Strait of Gibraltar and surrounding areas have shaped the present-day genomic diversity of its populations, we have performed a screening of 2.5 million single-nucleotide polymorphisms in 142 samples from southern Spain, southern Portugal, and Morocco. We built comprehensive data sets of the studied area and we implemented multistep bioinformatic approaches to assess population structure, demographic histories, and admixture dynamics. Both local and global ancestry inference showed an internal substructure in the Iberian Peninsula, mainly linked to a differential African ancestry. Western Iberia, from southern Portugal to Galicia, constituted an independent cluster within Iberia characterized by an enriched African genomic input. Migration time modeling showed recent historic dates for the admixture events occurring both in Iberia and in the North of Africa. However, an integrative vision of both paleogenomic and modern DNA data allowed us to detect chronological transitions and population turnovers that could be the result of transcontinental migrations dating back from Neolithic times. The present contribution aimed to fill the gaps in the modern human genomic record of a key geographic area, where the Mediterranean and the Atlantic come together.
Core–Shell Fibers: Design, Roles, and Controllable Release Strategies in Tissue Engineering and Drug Delivery

The key attributes of core–shell fibers are their ability to preserve bioactivity of incorporated-sensitive biomolecules (such as drug, protein, and growth factor) and subsequently control biomolecule release to the targeted microenvironments to achieve therapeutic effects. Such qualities are highly favorable for tissue engineering and drug delivery, and these features are not able to be offered by monolithic fibers. In this review, we begin with an overview on design requirement of core–shell fibers, followed by the summary of recent preparation methods of core–shell fibers, with focus on electrospinning-based techniques and other newly discovered fabrication approaches. We then highlight the importance and roles of core–shell fibers in tissue engineering and drug delivery, accompanied by thorough discussion on controllable release strategies of the incorporated bioactive molecules from the fibers. Ultimately, we touch on core–shell fibers-related challenges and offer perspectives on their future direction towards clinical applications.