Miracle-dz/UniFAR-FTUs huggingface dataset:
Cooperation between Different CRISPR-Cas Types Enables Adaptation in an RNA-Targeting System

CRISPR-Cas systems are immune systems that protect bacteria and archaea against their viruses, bacteriophages. Immunity is achieved through the acquisition of short DNA fragments from the viral invader’s genome. ABSTRACT CRISPR-Cas immune systems adapt to new threats by acquiring new spacers from invading nucleic acids such as phage genomes. However, some CRISPR-Cas loci lack genes necessary for spacer acquisition despite variation in spacer content between microbial strains. It has been suggested that such loci may use acquisition machinery from cooccurring CRISPR-Cas systems within the same strain. Here, following infection by a virulent phage with a double-stranded DNA (dsDNA) genome, we observed spacer acquisition in the native host Flavobacterium columnare that carries an acquisition-deficient CRISPR-Cas subtype VI-B system and a complete subtype II-C system. We show that the VI-B locus acquires spacers from both the bacterial and phage genomes, while the newly acquired II-C spacers mainly target the viral genome. Both loci preferably target the terminal end of the phage genome, with priming-like patterns around a preexisting II-C protospacer. Through gene deletion, we show that the RNA-cleaving VI-B system acquires spacers in trans using acquisition machinery from the DNA-cleaving II-C system. Our observations support the concept of cross talk between CRISPR-Cas systems and raise further questions regarding the plasticity of adaptation modules. IMPORTANCE CRISPR-Cas systems are immune systems that protect bacteria and archaea against their viruses, bacteriophages. Immunity is achieved through the acquisition of short DNA fragments from the viral invader’s genome. These fragments, called spacers, are integrated into a memory bank on the bacterial genome called the CRISPR array. The spacers allow for the recognition of the same invader upon subsequent infection. Most CRISPR-Cas systems target DNA, but recently, systems that exclusively target RNA have been discovered. RNA-targeting CRISPR-Cas systems often lack genes necessary for spacer acquisition, and it is thus unknown how new spacers are acquired and if they can be acquired from DNA phages. Here, we show that an RNA-targeting system “borrows” acquisition machinery from another CRISPR-Cas locus in the genome. Most new spacers in this locus are unable to target phage mRNA and are therefore likely redundant. Our results reveal collaboration between distinct CRISPR-Cas types and raise further questions on how other CRISPR-Cas loci may cooperate.
Tailoring the strong coupling regime in III‐nitride based microcavities for room temperature polariton laser applications

We report on the properties of III-nitride based microcavities (MCs) operating in the strong coupling regime (SCR) up to room temperature. We first discuss why this class of materials is well suited to investigate the physics of cavity polaritons, which are admixed particles resulting from the coupling between cavity photons and excitons. In addition to the high quality of the different building blocks forming the MC, we point out the role of the active medium geometry, and in particular, the impact of the quantum well number and the distribution of the latter to maximize the vacuum Rabi splitting. Thanks to a well grounded SCR at high temperatures, we demonstrate polariton lasing in the 180-340 K range whose threshold is mainly governed by thermally activated detrapping mechanisms. Since the trap depth formed by the lower polariton branch is fixed by the exciton-cavity photon detuning (delta), it is shown that the polariton escape rate from the trap and hence the threshold power density strongly depend on this parameter. Experimental results are well accounted for when using a simplified thermodynamic model that reproduces the threshold behavior as a function of gin the temperature range investigated.
Diabetes pathogenesis and management: the endothelium comes of age

Abstract Endothelium, acting as a barrier, protects tissues against factors that provoke insulin resistance and type 2 diabetes and itself responds to the insult of insulin resistance inducers with altered function. Endothelial insulin resistance and vascular dysfunction occur early in the evolution of insulin resistance-related disease, can co-exist with and even contribute to the development of metabolic insulin resistance, and promote vascular complications in those affected. The impact of endothelial insulin resistance and vascular dysfunction varies depending on the blood vessel size and location, resulting in decreased arterial plasticity, increased atherosclerosis and vascular resistance, and decreased tissue perfusion. Women with insulin resistance and diabetes are disproportionately impacted by cardiovascular disease, likely related to differential sex-hormone endothelium effects. Thus, reducing endothelial insulin resistance and improving endothelial function in the conduit arteries may reduce atherosclerotic complications, in the resistance arteries lead to better blood pressure control, and in the microvasculature lead to less microvascular complications and more effective tissue perfusion. Multiple diabetes therapeutic modalities, including medications and exercise training, improve endothelial insulin action and vascular function. This action may delay the onset of type 2 diabetes and/or its complications, making the vascular endothelium an attractive therapeutic target for type 2 diabetes and potentially type 1 diabetes.
Remembering sentences is not all about memory: Convergent and discriminant validity of syntactic knowledge and its relationship with reading comprehension

Abstract Recent studies have found correlations between sentence-level tests and reading comprehension. However, the task demands of sentence-level tests are not well understood. The present study investigated syntactic knowledge as a construct by examining the convergent and discriminant validity of two sentence-level tasks, sentence comprehension and sentence repetition, designed to test syntactic knowledge and their relation with reading comprehension. Results from 86 Grade 6 students showed that the syntax tests were more highly correlated with each other than with tests of working memory and vocabulary. This suggests that the syntax measures tap into a set of skills that are at least partially separate from these other cognitive constructs. Furthermore, syntactic knowledge explained unique variance in reading comprehension beyond controls. The syntax tasks were working memory dependent, but working memory was not the primary reason why syntax tasks are correlated with reading comprehension.
17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the “non‐feminizing” estrogen, 17‐α‐estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log‐rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang–Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex‐specific aspects of aging.
Scanning Kelvin probe study of (Oxyhydr)oxide surface of aluminum alloy

In this paper, the work function, referenced as electrode potential vs SHE, of modified (oxyhydr)oxide surfaces of AA1050 was studied upon exposure to different relative humidity (40% and 90%) and aging (40 and 240 min) by utilizing scanning Kelvin probe (SKP). Besides reference samples, different pretreatments (acid, alkaline, and immersion in boiling water) were applied in order to create variations in the surface properties (i.e., hydroxyl content, oxide thickness, surface morphology). The observed trend in the potential was correlated to the hydroxyl fraction and the oxide thickness of the modified surfaces, determined by X-ray photoelectron spectroscopy and visible spectroscopic ellipsometry , respectively. Fourier transform infrared spectroscopy was also used to investigate the chemical composition of the modified surfaces. It is presented how the surface potential of aluminum (oxyhydr)oxide is influenced by the oxide properties, such as hydroxyl fraction and thickness. This characterization work on.
Comparison of methodologies to detect hemoglobinopathy carriers in a multi‐ethnic sperm donor population

An estimated 7% of the world's population are carriers for a hemoglobin disorder. Current guidelines recommend carrier screening by complete blood count, with follow‐up hemoglobin electrophoresis or fractionation based on abnormal result or ethnicity. Advances in molecular genetic testing are thought to increase carrier detection. This study compares carrier screening methodologies in a multi‐ethnic sperm donor population. A retrospective analysis was conducted using data from a US sperm bank. All men underwent carrier screening for hemoglobin disorders via complete blood count, hemoglobin fractionation, and molecular testing. Results were compared using counts and percentages. McNemar's exact test was used to examine differences in the marginal probabilities of screening methodologies. Of the 438 tested, 25 (5.7%) were identified as carriers of at least one hemoglobin disorder by molecular testing. Seventeen (68%) of those carriers were missed by recommended methods. No identified carriers were detected by recommended methods but missed by molecular testing. The difference between these discordant pairs was significant (p‐value < 0.001). The majority (44%) of carriers were mixed ethnicity, followed by 36% White. Results indicate that molecular screening methodologies have a greater ability to detect carriers of hemoglobin disorders compared to currently recommended methods in a multi‐ethnic population.
Silicon in mitigation of abiotic stress-induced oxidative damage in plants

Abstract Accumulation of reactive oxygen species (ROS), and their destructive effects on cellular organelles are the hallmark features of plants exposed to abiotic stresses. Plants are well-equipped with defensive mechanisms like antioxidant systems to deal with ROS-induced oxidative stress. Silicon has been emerged as an important regulator of plant protective mechanisms under environmental stresses, which can be up-taken from soil through a system of various silicon-transporters. In plants, silicon is deposited underneath of cuticles and in the cell wall, and help plant cells reduce deleterious effects of stresses. Furthermore, silicon can provide resistance to ROS-toxicity, which often accounts for silicon-mediated improvement of plant tolerance to different abiotic constraints, including salinity, drought, and metal toxicity. Silicon enhances the ROS-detoxification ability of treated plants by modulating the antioxidant defense systems, and the expression of key genes associated with oxidative stress mitigation and hormone metabolism. Silicon also displays additive roles in ROS-elimination when supplied with other external stimuli. Here, we discuss recent findings on how silicon is able to modulate antioxidant defense of plants in response to oxidative stress triggered by different abiotic constraints. We also review interactions of silicon with other signaling molecules, including nitric oxide, ROS, polyamines, and phytohormones in the mediation of plant protection against abiotic stress-induced oxidative damage.
Lipid-based nano-formulation platform for eplerenone oral delivery as a potential treatment of chronic central serous chorioretinopathy: in-vitro optimization and ex-vivo assessment

Abstract Purpose Eplerenone (EPL) is a selective mineralocorticoid receptor antagonist used for treatment of chronic central serous chorioretinopathy which characterized by accumulation of subretinal fluid causing a localized area of retinal detachment. unfortunately, EPL suffers from poor oral bioavailability due to poor aqueous solubility in addition to high hepatic first pass metabolism. Method Aiming to improve its oral bioavailability, EPL-loaded nanostructured lipid carriers (NLCs) were prepared by the emulsification solvent evaporation method and in-vitro evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE%). A D-optimal design was used for study the effect of liquid lipid to solid lipid ratio, surfactant type and percentage on PS, PDI, EE%, and for data optimization. The optimized EPL-loaded NLCs system was further evaluated using in-vitro drug release and ex-vivo permeation studies through rabbit intestine in comparison to EPL aqueous suspension. The physicochemical properties of the drug in the optimized system were further examined using FT-IR and X-ray diffraction studies. Results The resultant NLCs showed small PS (100.85–346.60 nm), homogenous distribution (0.173–0.624), negatively charged particles (ZP −20.20 to −36.75 mV), in addition to EE% (34.31–70.64%). The optimized EPL-loaded NLCs system with a desirability value of 0.905 was suggested through the Design expert® software, containing liquid to solid lipid ratio (2:1) in presence of 0.43%w/v Pluronic® F127 as a surfactant. The optimized EPL-loaded NLCs system showed a PS of 134 nm and PDI of 0.31, in addition to high EE% (76 ± 6.56%w/w), and ZP (-32.37 mV). The ex-vivo permeation study showed two-fold higher drug permeation through rabbit intestine compared to that from the aqueous drug suspension after 24 h, confirming the ability of optimized EPL-loaded NLCs system as successful oral targeting delivery carrier. Conclusion Our results pave the way for a new oral nanotherapeutic approach toward CSCR treatment. In-vivo study is currently under investigation.
Standardized User-Independent Confocal Microscopy Image Acquisition and Analysis for Thickness Measurements of Microscale Collagen Scaffolds

Abstract The ability to accurately and precisely measure the thickness of biomaterial constructs is critical for characterizing both specific dimensional features and related mechanical properties. However, in the absence of a standardized approach for thickness measurements, a variety of imaging modalities have been employed, which have been associated with varying limits of accuracy, particularly for ultrathin hydrated structures. Electron microscopy (EM), a commonly used modality, yields thickness values for extensively processed and nonhydrated constructs, potentially resulting in overestimated mechanical properties, including elastic modulus and ultimate tensile strength. Confocal laser scanning microscopy (CLSM) has often been used as a nondestructive imaging alternative. However, published CLSM-derived image analysis protocols use arbitrary signal intensity cutoffs and provide minimal information regarding thickness variability across imaged surfaces. To address the aforementioned limitations, we present a standardized, user-independent CLSM image acquisition and analysis approach developed as a custom ImageJ macro and validated with collagen-based scaffolds. In the process, we also quantify thickness discrepancies in collagen-based scaffolds between CLSM and EM techniques, further illustrating the need for improved strategies. Employing the same image acquisition protocol, we also demonstrate that this approach can be used to estimate the surface roughness of the same scaffolds without the use of specialized instrumentation.
Foot Reanimation Using Double Nerve Transfer to Deep Peroneal Nerve: A Novel Technique for Treatment of Neurologic Foot Drop

Background: Our primary objective was to assess the efficacy of a new technique for foot reanimation in patients with neurologic foot drop using double nerve transfer from the tibial to the deep peroneal nerve. Our secondary objective was to document the technical nuances of our technique. Methods: Thirty-one patients with common peroneal nerve injury between October 2015 and March 2019 were prospectively enrolled in the study. Patients underwent a transfer of the tibial nerve branches to flexor digitorum longus and lateral head of gastrocnemius to the deep peroneal nerve. Motor recovery, range of ankle dorsiflexion, pain, leg girth, and complications were examined as outcome measures. The modified Medical Research Council (MRC) scale was adopted to assess the motor power recovery. All patients were followed up for a minimum of 1 year. Results: Motor recovery of M3 or M4 grade of tibialis anterior, extensor hallucis longus, and extensor digitorum longus was achieved in 15 of 31, 13 of 31, and 12 of 31 patients, respectively. Those patients could discontinue use of orthosis. Most patients with high-energy traumas or knee-level injuries failed to recover antigravity function. Only 2 patients reported weak postoperative toe plantarflexion. Our patients achieved significant improvement of the pain perception and range of active ankle motion at the final follow-up. Conclusion: The double nerve transfer technique represented a feasible and safe surgical option. It has been shown to improve function in some patients with neurologic foot drop resulting from a less than 12-month injury of the deep peroneal nerve. Level of Evidence: Level IV, therapeutic.
RPA2 winged-helix domain facilitates UNG-mediated removal of uracil from ssDNA; implications for repair of mutagenic uracil at the replication fork

Abstract Uracil occurs at replication forks via misincorporation of deoxyuridine monophosphate (dUMP) or via deamination of existing cytosines, which occurs 2–3 orders of magnitude faster in ssDNA than in dsDNA and is 100% miscoding. Tethering of UNG2 to proliferating cell nuclear antigen (PCNA) allows rapid post-replicative removal of misincorporated uracil, but potential ‘pre-replicative’ removal of deaminated cytosines in ssDNA has been questioned since this could mediate mutagenic translesion synthesis and induction of double-strand breaks. Here, we demonstrate that uracil-DNA glycosylase (UNG), but not SMUG1 efficiently excises uracil from replication protein A (RPA)-coated ssDNA and that this depends on functional interaction between the flexible winged-helix (WH) domain of RPA2 and the N-terminal RPA-binding helix in UNG. This functional interaction is promoted by mono-ubiquitination and diminished by cell-cycle regulated phosphorylations on UNG. Six other human proteins bind the RPA2-WH domain, all of which are involved in DNA repair and replication fork remodelling. Based on this and the recent discovery of the AP site crosslinking protein HMCES, we propose an integrated model in which templated repair of uracil and potentially other mutagenic base lesions in ssDNA at the replication fork, is orchestrated by RPA. The UNG:RPA2-WH interaction may also play a role in adaptive immunity by promoting efficient excision of AID-induced uracils in transcribed immunoglobulin loci.
Most Genomic Loci Misrepresent the Phylogeny of an Avian Radiation Because of Ancient Gene Flow

Abstract Phylogenetic trees based on genome-wide sequence data may not always represent the true evolutionary history for a variety of reasons. One process that can lead to incorrect reconstruction of species phylogenies is gene flow, especially if interspecific gene flow has affected large parts of the genome. We investigated phylogenetic relationships within a clade comprising eight species of passerine birds (Phylloscopidae, Phylloscopus, leaf warblers) using one de novo genome assembly and 78 resequenced genomes. On the basis of hypothesis-exclusion trials based on D-statistics, phylogenetic network analysis, and demographic inference analysis, we identified ancient gene flow affecting large parts of the genome between one species and the ancestral lineage of a sister species pair. This ancient gene flow consistently caused erroneous reconstruction of the phylogeny when using large amounts of genome-wide sequence data. In contrast, the true relationships were captured when smaller parts of the genome were analyzed, showing that the “winner-takes-all democratic majority tree” is not necessarily the true species tree. Under this condition, smaller amounts of data may sometimes avoid the effects of gene flow due to stochastic sampling, as hidden reticulation histories are more likely to emerge from the use of larger data sets, especially whole-genome data sets. In addition, we also found that genomic regions affected by ancient gene flow generally exhibited higher genomic differentiation but a lower recombination rate and nucleotide diversity. Our study highlights the importance of considering reticulation in phylogenetic reconstructions in the genomic era. [Bifurcation; introgression; recombination; reticulation; Phylloscopus. ]
The Short- and Long-Term Impact of Pulmonary Rehabilitation in Subjects with Sarcoidosis: A Prospective Study and Review of the Literature

Background: Sarcoidosis is a heterogeneous multisystemic disorder of unknown etiology. Dyspnea and fatigue are two of the most common and debilitating symptoms experienced by subjects with sarcoidosis. There is limited evidence regarding the short- and long-term impact of pulmonary rehabilitation (PR) on exercise capacity and fatigue in these individuals. Objective: To evaluate the benefit of PR in subjects with pulmonary sarcoidosis at different severity stages and to review the current literature about PR in sarcoidosis. Methods: PR included a 12-week training program of a twice-weekly 90-min workouts. Fifty-two subjects with stable pulmonary sarcoidosis were recruited. Maximal exercise capacity, defined as VO2max, was measured using the cardiopulmonary exercise test (CPET). Pulmonary function tests, 6-min walking distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ), and the modified Medical Research Council (mMRC) and Hospital Anxiety and Depression Scale (HADS) questionnaires were given before and after PR and following 6 months (follow-up). Results: The PR program significantly increased the VO2max (1.8 ± 2.3 mL/kg/min, p = 0.002), following 12 weeks. mMRC and SGRQ scores were also improved (−0.3 ± 0.8, p = 0.03, and −3.87 ± 10.4, p = 0.03, respectively). The impact of PR on VO2max was more pronounced in subjects with pulmonary parenchymal involvement. The increase in VO2max correlated with initial disease severity (indicated by FEV1/FVC, p = 0.01). Subjects with FEV1/FVC <70% showed greater improvement in 6MWD. 6MWD also improved in those with a transfer coefficient of the lung for CO (KCO) above 80% predicted (p < 0.05). At 6-month follow-up, the VO2max, 6MWD, and SGRQ scores remained stable, thus suggesting lasting effects of PR. Conclusion: PR is a promising complementary therapeutic intervention for subjects with sarcoidosis. Further study is needed to validate these findings.