Miracle-dz/UniFAR-FTUs huggingface dataset:
Nanovesicle-Mediated Delivery Systems for CRISPR/Cas Genome Editing

Genome-editing technology has emerged as a potential tool for treating incurable diseases for which few therapeutic modalities are available. In particular, discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system together with the design of single-guide RNAs (sgRNAs) has sparked medical applications of genome editing. Despite the great promise of the CRISPR/Cas system, its clinical application is limited, in large part, by the lack of adequate delivery technology. To overcome this limitation, researchers have investigated various systems, including viral and nonviral vectors, for delivery of CRISPR/Cas and sgRNA into cells. Among nonviral delivery systems that have been studied are nanovesicles based on lipids, polymers, peptides, and extracellular vesicles. These nanovesicles have been designed to increase the delivery of CRISPR/Cas and sgRNA through endosome escape or using various stimuli such as light, pH, and environmental features. This review covers the latest research trends in nonviral, nanovesicle-based delivery systems that are being applied to genome-editing technology and suggests directions for future progress.
Carrier concentration profiling on oxidized surfaces of Si device cross sections by resonant electron tunneling scanning probe spectroscopy

Quantitative carrier concentration profiles of super-junction power metal-oxide-semiconductor field-effect transistor devices were obtained by resonant electron tunneling (RET) scanning probe spectroscopy making use of a discrete energy level of adsorbed C60 molecules. RET voltage profiles measured on oxidized (100) surfaces of fine-polished cross sections revealed the presence of separated p-type islands in the n-type epitaxial layer and agreed well with the profiles obtained by local work function spectroscopy, although fluctuations were observed owing to surface defects and variations in the oxide and C60 film thickness. The derived boron concentration coincides with the implanted boron density obtained by numerical simulations. These results verify that the C60 RET scanning probe spectroscopy on oxidized surfaces has the ability of quantitative carrier concentration profiling of Si device cross sections, if flat surfaces with good quality are prepared.
Application of near-infrared spectroscopy for the rapid analysis of Lonicerae Japonicae Flos solution extracted by water

A rapid quantitative analytical method for three components of Lonicerae Japonicae Flos solution (Lonicera Japonica Thumb.) extracted by water was developed using near-infrared (NIR) spectroscopy and the partial least-squares (PLS) method. The NIR spectra of 81 samples collected from a production line were obtained. The concentrations of secologanic acid, chlorogenic acid and galuteolin were determined by using high-performance liquid chromatography-diode array detection as the reference method. Several pretreatment methods for the NIR spectra were used during PLS calibration. The most appropriate latent variable number of the PLS factor was selected based on the standard error of cross-validation (SECV). The performance of the final PLS models was evaluated according to SECV, standard error of prediction (SEP) and determination coefficient (R2). The compounds secologanic acid, chlorogenic acid and galuteolin had SEP values of 0.030, 0.061 and 1.668 μg/mL, respectively and R2 values over 0.85. This work shows that NIR spectroscopy is a rapid and convenient method for the analysis of Lonicerae Japonicae Flos solution extracted by water. The proposed method can help in the application of process analytical technology in the pharmaceutical industry, particularly in traditional Chinese medicine injections.
CXCL6 fuels the growth and metastases of esophageal squamous cell carcinoma cells both in vitro and in vivo through upregulation of PD‐L1 via activation of STAT3 pathway

CXCL6, contraction of C‐X‐C motif chemokine ligand 6, whose biological roles have been rarely described in esophageal squamous cell carcinoma (ESCC). To understand the clinicopathological and biological roles played by CXCL6 in the growth and metastasis of ESCC, immunohistochemistry was used to detect the expression of CXCL6 in ESCC tissues, totaling 105 cases; and the correlation was statistically analyzed between CXCL6 expression and clinicopathological parameters. The role mediated in migration and invasion was evaluated using wound‐healing and Transwell assays. MTT and flow cytometry were used to assay the proliferative variation. In vivo, tail vein injection model was established in nude mice xenografted with human ESCC cell lines whose CXCL6 were artificially manipulated. It was found that relative to normal control, CXCL6 was profoundly higher in ESCC; upregulated CXCL6 only significantly correlated with differentiation degree. In vitro, CXCL6 was found to promote the proliferation, migration, and invasion of ESCC cells; which was fully corroborated by nude mice experiment that CXCL6 can promote the growth and metastases of ESCC cells in vivo. Mechanistically, CXCL6 was discovered to be capable of promoting epithelial‐mesenchymal transition and upregulating PD‐L1 expression through activation of the STAT3 pathway. Collectively, all the data we showed here demonstrate that CXCL6 can enhance the growth and metastases of ESCC cells both in vivo and in vitro.
Alleviation of extensive visual pathway dysfunction by a remyelinating drug in a chronic mouse model of multiple sclerosis

Visual deficits are among the most prevalent symptoms in patients with multiple sclerosis (MS). To understand deficits in the visual pathway during MS and potential treatment effects, we used experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The afferent visual pathway was assessed in vivo using optical coherence tomography (OCT), electroretinography (ERG), and visually evoked cortical potentials (VEPs). Inflammation, demyelination, and neurodegeneration were examined by immunohistochemistry ex vivo. In addition, an immunomodulatory, remyelinating agent, the estrogen receptor β ligand chloroindazole (IndCl), was tested for its therapeutic potential in the visual pathway. EAE produced functional deficits in visual system electrophysiology, including suppression of ERG and VEP waveform amplitudes and increased signal latencies. Therapeutic IndCl rescued overall visual system latency by VEP but had little impact on amplitude or ERG findings relative to vehicle. Faster VEP conduction in IndCl‐treated mice was associated with enhanced myelin basic protein signal in all visual system structures examined. IndCl preserved retinal ganglion cells (RGCs) and oligodendrocyte density in the prechiasmatic white matter, but similar retinal nerve fiber layer thinning by OCT was noted in vehicle and IndCl‐treated mice. Although IndCl differentially attenuated leukocyte and astrocyte staining signal throughout the structures analyzed, axolemmal varicosities were observed in all visual fiber tracts of mice with EAE irrespective of treatment, suggesting impaired axonal energy homeostasis. These data support incomplete functional recovery of VEP amplitude with IndCl, as fiber tracts displayed persistent axon pathology despite remyelination‐induced decreases in latencies, evidenced by reduced optic nerve g‐ratio in IndCl‐treated mice. Although additional studies are required, these findings demonstrate the dynamics of visual pathway dysfunction and disability during EAE, along with the importance of early treatment to mitigate EAE‐induced axon damage.
The nucleotide prodrug CERC‐913 improves mtDNA content in primary hepatocytes from DGUOK‐deficient rats

Loss‐of‐function mutations in the deoxyguanosine kinase (DGUOK) gene result in a mitochondrial DNA (mtDNA) depletion syndrome. DGUOK plays an important role in converting deoxyribonucleosides to deoxyribonucleoside monophosphates via the salvage pathway for mtDNA synthesis. DGUOK deficiency manifests predominantly in the liver; the most common cause of death is liver failure within the first year of life and no therapeutic options are currently available. in vitro supplementation with deoxyguanosine or deoxyguanosine monophosphate (dGMP) were reported to rescue mtDNA depletion in DGUOK‐deficient, patient‐derived fibroblasts and myoblasts. CERC‐913, a novel ProTide prodrug of dGMP, was designed to bypass defective DGUOK while improving permeability and stability relative to nucleoside monophosphates. To evaluate CERC‐913 for its ability to rescue mtDNA depletion, we developed a primary hepatocyte culture model using liver tissue from DGUOK‐deficient rats. DGUOK knockout rat hepatocyte cultures exhibit severely reduced mtDNA copy number (~10%) relative to wild type by qPCR and mtDNA content remains stable for up to 8 days in culture. CERC‐913 increased mtDNA content in DGUOK‐deficient hepatocytes up to 2.4‐fold after 4 days of treatment in a dose‐dependent fashion, which was significantly more effective than dGMP at similar concentrations. These early results suggest primary hepatocyte culture is a useful model for the study of mtDNA depletion syndromes and that CERC‐913 treatment can improve mtDNA content in this model.
Contribution of Executive Functions to Learning Sequential Actions in Young Children.

This study examined whether executive functions impact how flexibly children represent task context in performing repeated sequential actions. Japanese children in Experiments 1 (N = 52; 3-6 years) and 2 (N = 50, 4-6 years) performed sequential actions repeatedly; one group received reminders. Experiment 1 indicated that reminders promote flexible changes in contextual representations. Experiment 2 observed such effects in younger children and showed executive functions were associated with the flexible representation of task context. Reminders did not perfectly compensate for the role of executive functions but wiped out individual differences in executive functions that contribute to children's acquisition of routines. Therefore, setting goals before context-dependent actions is necessary, but not sufficient, to modulate contextual representations in routines.
Daratumumab monotherapy for relapsed/refractory multiple myeloma, focussed on clinical trial‐unfit patients and subsequent therapy

Real‐world outcomes of daratumumab monotherapy (DM) for relapsed/refractory multiple myeloma (RRMM) have remained unclear. We conducted a multicentre retrospective study of 107 patients receiving DM for RRMM. The cohort included 64 trial‐unfit patients whose characteristics could not meet inclusion criteria in two previous clinical trials (GEN501 and SIRIUS). The overall response rate (ORR), and median first and second progression‐free survival (PFS1 and PFS2) and overall survival were 42·1%, and 3·6, 8·1 and 11·9 months, respectively. Refractoriness to carfilzomib and/or lenalidomide, and neutropenia (<1.0 × 109/l) resulted in poorer ORRs. An Eastern Cooperative Oncology Group Performance Status of ≥3, neutropenia (<1.0 × 109/l), thrombocytopenia (<75 × 109/l), and renal failure (glomerular filtration rate of <20 ml/min/1·73 m2) were associated with poor PFS1 and PFS2 in respective univariate analysis. The modified trial‐unfit group, based on the above factors, showed significantly negative impacts on PFS1 and PFS2 (hazard ratio 2·823 and 3·677, all P < 0·001) in multivariate analysis despite having a 34% ORR. Fatal infections occurred more often in the modified trial‐unfit group than in the others (16·1% vs. 4·3%; P = 0·099). Despite failure of DM, subsequent therapy with pomalidomide‐based therapy or carfilzomib‐dexamethasone provided a 66·6% ORR. Real‐world DM showed favourable efficacies for RRMM and, potentially, additional benefits with subsequent therapies. However, characteristics corresponding with trial‐unfitness might offset the efficacy of DM.
Iridium Complexes with Phosphine-Phosphite Ligands. Structural Aspects and Application in the Catalytic Asymmetric Hydrogenation of N-Aryl Imines

A family of modularly designed phosphine−phosphites (P−OP), possessing a C−C−O backbone, has been synthesized and evaluated in the iridium-catalyzed asymmetric hydrogenation of N-aryl imines. The enantioselectivity of this reaction is highly dependent on the nature of the ligand, and catalysts bridged by an oxyethylene fragment have produced significantly higher enantiomeric excesses (Δee > 20%) than their o-oxyphenylene counterparts. Structural studies by X-ray crystallography and NMR spectroscopy of complexes with the formulation [Ir(COD)(P−OP)]BF4 and Ir(Cl)(CO)(P−OP), complemented by DFT calculations of model compounds of the chlorocarbonyls, have shown important differences between complexes bridged by an aliphatic or an aromatic bridge, regarding the iridacycle conformation and the location of phosphine substituents. Catalyst optimization has afforded enantioselectivities from 72 to 85% ee in the hydrogenation of several N-aryl imines.
Quality of life in adults with achondroplasia in the United States

Studies examining quality of life (QoL) in adults with achondroplasia are limited. We report on QoL and psychiatric illness diagnoses in a modern cohort of adults with achondroplasia. SF‐36 Health Survey scores from adults with achondroplasia were compared to general population scores. Demographics, physical measurements, and psychiatric illness diagnoses were recorded from medical records. The achondroplasia population had lower scores than the general population in all categories. Most people with achondroplasia (56%) had a diagnosed psychiatric illness. Those with a diagnosed psychiatric illness had lower scores in physical functioning, role limitations due to physical and emotional health, and mental health. Pain, energy/fatigue, and general health scale scores were roughly equivalent (<2 points difference). Social functioning was >15 points higher in individuals with psychiatric illness diagnoses. Adults with achondroplasia report significantly lower physical and mental well‐being and had nearly 3× the rate of psychiatric illness diagnosis than the general population, highlighting the importance of total care for this population. Healthcare providers must understand the physical and mental comorbidities of achondroplasia, beyond short stature and orthopedic issues, so they can proactively improve QoL across the lifespan for patients and families.
IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?

IQSEC2 mutations are associated with IQSEC2‐related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype–phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2‐related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype–phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate‐to‐mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2‐associated phenotype delineation.
UV Raman Demonstrates that α-Helical Polyalanine Peptides Melt to Polyproline II Conformations

We examined the 204-nm UV Raman spectra of the peptide XAO, which was previously found by Shi et al.'s NMR study to occur in aqueous solution in a polyproline II (PPII) conformation. The UV Raman spectra of XAO are essentially identical to the spectra of small peptides such as ala(5) and to the large 21-residue predominantly Ala peptide, AP. We conclude that the non-alpha-helical conformations of these peptides are dominantly PPII. Thus, AP, which is highly alpha-helical at room temperature, melts to a PPII conformation. There is no indication of any population of intermediate disordered conformations. We continued our development of methods to relate the Ramachandran Psi-angle to the amide III band frequency. We describe a new method to estimate the Ramachandran Psi-angular distributions from amide III band line shapes measured in 204-nm UV Raman spectra. We used this method to compare the Psi-distributions in XAO, ala(5), the non-alpha-helical state of AP, and acid-denatured apomyoglobin. In addition, we estimated the Psi-angle distributions of peptide bonds which occur in non-alpha-helix and non-beta-sheet conformations in a small library of proteins.
FRET‐MC: A fluorescence melting competition assay for studying G4 structures in vitro

G‐quadruplexes (G4) play crucial roles in biology, analytical chemistry and nanotechnology. The stability of G4 structures is impacted by the number of G‐quartets, the length and positions of loops, flanking motifs, as well as additional structural elements such as bulges, capping base pairs, or triads. Algorithms such as G4Hunter or Quadparser may predict if a given sequence is G4‐prone by calculating a quadruplex propensity score; however, experimental validation is still required. We previously demonstrated that this validation is not always straightforward, and that a combination of techniques is often required to unambiguously establish whether a sequence forms a G‐quadruplex or not. In this article, we adapted the well‐known FRET‐melting assay to characterize G4 in batch, where the sequence to be tested is added, as an unlabeled competitor, to a system composed of a dual‐labeled probe (F21T) and a specific quadruplex ligand. PhenDC3 was preferred over TMPyP4 because of its better selectivity for G‐quadruplexes. In this so‐called FRET‐MC (melting competition) assay, G4‐forming competitors lead to a marked decrease of the ligand‐induced stabilization effect (∆Tm), while non‐specific competitors (e.g., single‐ or double‐stranded sequences) have little effect. Sixty‐five known sequences with different typical secondary structures were used to validate the assay, which was subsequently employed to assess eight novel sequences that were not previously characterized.
Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD‐L1 expression by C5a

The treatment of castration‐resistant prostate cancer (CRPC) is a urological issue. Recent studies have revealed cancer promotion via the C5a–C5a receptor (C5aR) system. To establish a new therapeutic target for CRPC, we investigated an association of the system with CRPC progression and evasion from the antitumor immune responses.
Syntheses and Transformations of Sulfoximines

Sulfoximines are widely used as medicines, agricultural chemicals, chiral precursors, and chiral ligands in asymmetric synthesis, as well as pivotal intermediates for the construction of heterocyclic compounds. NH‐sulfoximines may be synthesized from thioethers, sulfoxides, sulfilimines, and sulfinamides. NH‐sulfoximines can undergo various transformations, such as arylations, alkylations, vinylations, and alkynylations. Here, we review the methods that have been applied to the syntheses and transformations of NH‐sulfoximines.
Characterization of a novel allele encoding pheophorbide a oxygenase in rice

ABSTRACT We identified a rapid cell death 2 (rcd2) mutant from an indica cultivar Zhongjian100 mutant bank. The red-brown lesions appeared firstly on young seedling leaves, then gradually merged and the leaves completely withered at the late tillering stage. rcd2 displayed apparent cell death at/around the lesions, accumulation of superoxide anion (O2 −) and disturbed ROS scavenging system, impaired photosynthetic capacity with significantly reduced chlorophyll content. The lesion formation was controlled by a single recessive nuclear gene and induced by natural light as well as mechanical wounding. A single base mutation (A1726T) at the 6th exon of OsMH_03G0040800 resulted in I576F substitution in the encoding protein, pheophorbide a oxygenase (PAO). Functional complementation could rescue the mutant phenotype and PAO-knockout lines exhibited the similar phenotype to rcd2. The activity of PAO decreased significantly while the content of PAO substrate, pheophorbide a, increased apparently in rcd2. The expression of chlorophyll synthesis/degradation-related genes and the contents of metabolic intermediates were largely changed. Furthermore, the level of chlorophyllide a, the product of chlorophyllase, increased significantly, indicating chlorophyllase might play a role in chlorophyll degradation in rice. Our results suggested that the I576F substitution disrupted PAO function, leading to O2 − accumulation and chlorophyll degradation breakdown in rice.
Theta Synchrony Is Increased near Neural Populations That Are Active When Initiating Instructed Movement

Abstract Theta oscillations (3–8 Hz) in the human brain have been linked to perception, cognitive control, and spatial memory, but their relation to the motor system is less clear. We tested the hypothesis that theta oscillations coordinate distributed behaviorally relevant neural representations during movement using intracranial electroencephalography (iEEG) recordings from nine patients (n = 490 electrodes) as they performed a simple instructed movement task. Using high frequency activity (HFA; 70–200 Hz) as a marker of local spiking activity, we identified electrodes that were positioned near neural populations that showed increased activity during instruction and movement. We found that theta synchrony was widespread throughout the brain but was increased near regions that showed movement-related increases in neural activity. These results support the view that theta oscillations represent a general property of brain activity that may also play a specific role in coordinating widespread neural activity when initiating voluntary movement.
TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia

Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near‐normal patient life‐expectancy; however, quality of life and aggravation of existing co‐morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective ‘real‐world practice’ review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow‐up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow‐up. Seventy‐six patients eventually discontinued LD TKI and the two‐year treatment‐free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.
Psychiatric symptoms during the COVID‐19 outbreak in older adults with bipolar disorder

Older adults with bipolar disorder (OABD) are vulnerable for a COVID‐19 infection via multiple pathways. It is essential for OABD to adhere to the COVID‐19 measures, with potential consequences for the psychiatric symptoms. This situation offers the unique opportunity to investigate factors of vulnerability and resilience that are associated with psychiatric symptoms in OABD.