Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetic–pharmacodynamic modeling for hepatic delivery and efficacy of antisense oligonucleotides with lipophilic ligands in mice

Conjugation with lipophilic ligands such as cholesterol and α‐tocopherol dramatically improves the delivery and efficacy of antisense oligonucleotides (ASOs) in the liver. To estimate the hepatic ASO concentration and the efficacy of ASOs conjugated with lipophilic ligands in mice, we constructed a pharmacokinetic‐pharmacodynamic (PK‐PD) model that consisted of a two‐linear compartment model for the plasma and the hepatic ASO concentration, and two indirect response models for the hepatic apolipoprotein B (Apo‐B) mRNA and plasma total cholesterol. The model provided a good fit of the hepatic ASO concentration although it showed an overprediction of Apo‐B mRNA and an underprediction of the plasma total cholesterol within 2‐fold at a later time after single intravenous administration of ASOs conjugated with lipophilic ligands. In addition, the model simulations indicated that the efficacy at a dose regimen of ASOs conjugated with lipophilic ligands (0.2 mg/kg, once a week) in mice was comparable to that at an effective dose of unchanged ASO (2.5 mg/kg, once a week). Although further studies are required to refine the parameters of the PK–PD model, this approach could be used to guide dose‐ranging pharmacological studies for ASOs conjugated with lipophilic ligands in mice.
Subgenomic RNA identification in SARS-CoV-2 genomic sequencing data

We have developed periscope, a tool for the detection and quantification of subgenomic RNA (sgRNA) in SARS-CoV-2 genomic sequence data. The translation of the SARS-CoV-2 RNA genome for most open reading frames (ORFs) occurs via RNA intermediates termed “subgenomic RNAs. ” sgRNAs are produced through discontinuous transcription, which relies on homology between transcription regulatory sequences (TRS-B) upstream of the ORF start codons and that of the TRS-L, which is located in the 5′ UTR. TRS-L is immediately preceded by a leader sequence. This leader sequence is therefore found at the 5′ end of all sgRNA. We applied periscope to 1155 SARS-CoV-2 genomes from Sheffield, United Kingdom, and validated our findings using orthogonal data sets and in vitro cell systems. By using a simple local alignment to detect reads that contain the leader sequence, we were able to identify and quantify reads arising from canonical and noncanonical sgRNA. We were able to detect all canonical sgRNAs at the expected abundances, with the exception of ORF10. A number of recurrent noncanonical sgRNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sgRNA analysis. In VeroE6 ACE2+/− cell lines, periscope can detect the changes in the kinetics of sgRNA in orthogonal sequencing data sets. Finally, variants found in genomic RNA are transmitted to sgRNAs with high fidelity in most cases. This tool can be applied to all sequenced COVID-19 samples worldwide to provide comprehensive analysis of SARS-CoV-2 sgRNA.
A novel angiographic classification for the endovascular recanalization of symptomatic nonacute extracranial vertebral artery occlusion

Background There remains major uncertainty regarding the optimal therapy for symptomatic nonacute extracranial vertebral artery occlusion (EVAO). Endovascular recanalization for EVAO is technically challenging, and limited data are available. This research aimed to report a multicenter clinical experience of endovascular recanalization for symptomatic nonacute EVAO and establish a novel angiographic classification. Methods From June 2011 to December 2019, 50 symptomatic nonacute EVAO patients treated with endovascular recanalization in three regional referral stroke centers were retrospectively analyzed. All patients were categorized into four groups based on the angiographic classification. The rates of technical success, periprocedural complications, any stroke or death within 1 month, and follow-up data were assessed. Results The rates of technical success, periprocedural complications, and any stroke or death within 1 month were 86.0% (43/50), 12.0% (6/50), and 4.0% (2/50), respectively. The recanalization rates gradually decreased from Type A to Type D (100%, 94.7%, 80%, and 63.6%, respectively; P=0.007). The EVAO patients in the Type A group with tapered stump and short-segment occlusions showed excellent recanalization effects, with 100% technical success rates and no complications. Conversely, the lowest recanalization rate of 63.6% (7/11) and the highest periprocedural complication rate of 27.3% (3/11) were observed for the Type D group. Conclusions Endovascular recanalization for symptomatic nonacute EVAO is technically feasible, especially Type A EVAO patients, which can provide an alternative treatment option for recurrent vertebrobasilar ischemia despite optimal medical therapy. The angiographic categorization established in this study is conducive to the selection of suitable patients prior to treatment decision.
Distinct burst properties contribute to the functional diversity of thalamic nuclei

Thalamic neurons fire spikes in two modes, burst and tonic. The function of burst firing is unclear, but the evidence suggests that bursts are more effective at activating cortical cells, and that postinhibition rebound bursting contributes to thalamocortical oscillations during sleep. Bursts are considered stereotyped signals; however, there is limited evidence regarding how burst properties compare across thalamic nuclei of different functional or anatomical organization. Here, we used whole‐cell patch clamp recordings and compartmental modeling to investigate the properties of bursts in six sensory thalamic nuclei, to study the mechanisms that can lead to different burst properties, and to assess the implications of different burst properties for thalamocortical transmission and oscillatory functions. We found that bursts in higher‐order cells on average had higher number of spikes and longer latency to the first spike. Additionally, burst features in first‐order neurons were determined by sensory modality. Shifting the voltage‐dependence and density of the T‐channel conductance in a compartmental model replicates the burst properties from the intracellular recordings, pointing to molecular mechanisms that can generate burst diversity. Furthermore, the model predicts that bursts with higher number of spikes will drastically reduce the effectiveness of thalamocortical transmission. In addition, the latency to burst limited the rebound oscillatory frequency in modeled cells. These results demonstrate that burst properties vary according to the thalamocortical hierarchy and with sensory modality. The findings imply that, while in burst mode, thalamocortical transmission and firing frequency will be determined by the number of spikes and latency to burst.
Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

Gastric cancer (GC) pathogenesis is complex and heterogeneous, reflecting morphological, molecular and genetic diversity. Diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC) are the major histological types. GC may be sporadic or hereditary; sporadic GC is related to environmental and genetic low‐risk factors and hereditary GC is caused by inherited high‐risk mutations, so far identified only for the diffuse histotype. DGC phenotypic heterogeneity challenges the current understanding of molecular mechanisms underlying carcinogenesis. The definition of a DGC‐specific mutational profile remains controversial, possibly reflecting the heterogeneity of DGC‐related histological subtypes [signet‐ring cell carcinoma (SRCC) and poorly cohesive carcinoma not otherwise specified (PCC‐NOS)]. Indeed, DGC and DGC‐related subtypes may present specific mutational profiles underlying the particularly aggressive behaviour and dismal prognosis of DGC vs IGC and PCC‐NOS vs SRCC. In this systematic review, we revised the histological presentations, molecular classifications and approved therapies for gastric cancer, with a focus on DGC. We then analysed results from the most relevant studies, reporting mutational analysis data specifying mutational frequencies, and their relationship with DGC and IGC histological types, and with specific DGC subtypes (SRCC and PCC‐NOS). We aimed at identifying histology‐associated mutational profiles with an emphasis in DGC and its subtypes (DGC vs IGC; sporadic vs hereditary DGC; and SRCC vs PCC‐NOS). We further used these mutational profiles to identify the most commonly affected molecular pathways and biological functions, and explored the clinical trials directed specifically to patients with DGC. This systematic analysis is expected to expose a DGC‐specific molecular profile and shed light into potential targets for therapeutic intervention, which are currently missing.
The velvet protein Vel1 controls initial plant root colonization and conidia formation for xylem distribution in Verticillium wilt

The conserved fungal velvet family regulatory proteins link development and secondary metabolite production. The velvet domain for DNA binding and dimerization is similar to the structure of the Rel homology domain of the mammalian NF-κB transcription factor. A comprehensive study addressed the functions of all four homologs of velvet domain encoding genes in the fungal life cycle of the soil-borne plant pathogenic fungus Verticillium dahliae. Genetic, cell biological, proteomic and metabolomic analyses of Vel1, Vel2, Vel3 and Vos1 were combined with plant pathogenicity experiments. Different phases of fungal growth, development and pathogenicity require V. dahliae velvet proteins, including Vel1-Vel2, Vel2-Vos1 and Vel3-Vos1 heterodimers, which are already present during vegetative hyphal growth. The major novel finding of this study is that Vel1 is necessary for initial plant root colonization and together with Vel3 for propagation in planta by conidiation. Vel1 is needed for disease symptom induction in tomato. Vel1, Vel2, and Vel3 control the formation of microsclerotia in senescent plants. Vel1 is the most important among all four V. dahliae velvet proteins with a wide variety of functions during all phases of the fungal life cycle in as well as ex planta.
Characterizing the immune response of chickens to Campylobacter jejuni (Strain A74C)

Campylobacter is one of the major foodborne pathogens causing bacterial gastroenteritis worldwide. The immune response of broiler chickens to C. jejuni is under-researched. This study aimed to characterize the immune response of chickens to Campylobacter jejuni colonization. Birds were challenged orally with 0.5 mL of 2.4 x 108 CFU/mL of Campylobacter jejuni or with 0.5 mL of 0.85% saline. Campylobacter jejuni persisted in the ceca of challenged birds with cecal colonization reaching 4.9 log10 CFU/g on 21 dpi. Campylobacter was disseminated to the spleen and liver on 7 dpi and was cleared on 21 dpi from both internal organs. Challenged birds had a significant increase in anti-Campylobacter serum IgY (14&21 dpi) and bile IgA (14 dpi). At 3 dpi, there was a significant suppression in T-lymphocytes derived from the cecal tonsils of birds in the challenge treatment when compared to the control treatment after 72 h of ex vivo stimulation with Con A or C. jejuni. The T-cell suppression on 3 dpi was accompanied by a significant decrease in LITAF, K60, CLAU-2, IL-1β, iNOS, and IL-6 mRNA levels in the ceca and an increase in nitric oxide production from adherent splenocytes of challenged birds. In addition, on 3 dpi, there was a significant increase in CD4+ and CD8+ T lymphocytes in the challenge treatment. On 14 dpi, both pro and anti-inflammatory cytokines were upregulated in the spleen, and a significant increase in CD8+ T lymphocytes in Campylobacter-challenged birds’ ceca was observed. The persistence of C. jejuni in the ceca of challenged birds on 21 dpi was accompanied by an increase in IL-10 and LITAF mRNA levels, an increase in MNC proliferation when stimulated ex-vivo with the diluted C. jejuni, an increase in serum specific IgY antibodies, an increase in both CD4+ and CD8+ cells, and a decrease in CD4+:CD8+ cell ratio. The balanced Th1 and Th2 immune responses against C. jejuni might explain the ceca’s bacterial colonization and the absence of pathology in Campylobacter-challenged birds. Future studies on T lymphocyte subpopulations should elucidate a pivotal role in the persistence of Campylobacter in the ceca.
Inhibition‐directed multimodal imaging fusion patterns in adults with ADHD and its potential underlying “gene‐brain‐cognition” relationship

Inhibition deficits have been suggested to be a core cognitive impairment in attention‐deficit/hyperactivity disorder (ADHD). Exploring imaging patterns and the potential genetic components associated with inhibition deficits would definitely promote our understanding of the neuropathological mechanism of ADHD. This study aims to investigate the multimodal imaging fusion features related to inhibition deficits in adults with ADHD (aADHD) and to make an exploratory analysis of the role of inhibition‐related gene, NOS1, on those brain alterations.
Definition and time course of pericavity edema after minimally invasive endoscopic intracerebral hemorrhage evacuation

Background Perihematomal edema (PHE) volume correlates with intracerebral hemorrhage (ICH) volume and is associated with functional outcome. Minimally invasive surgery (MIS) for ICH decreases clot burden and PHE. MIS may therefore alter the time course of PHE, mitigating a critical source of secondary injury. Objective To describe a new method for the quantitative measurement of cerebral edema surrounding the evacuated hematoma cavity, termed pericavity edema (PCE), and obtain details of its time course following MIS for ICH. Methods The study included 48 consecutive patients presenting with ICH who underwent MIS evacuation. Preoperative and postoperative CT scans were assessed by two independent raters. Hematoma, edema, cavity, and pneumocephalus volumes were calculated using semi-automatic, threshold-guided volume segmentation software (AnalyzePro). Follow-up CT scans at variable delayed time points were available for 36 patients and were used to describe the time course of PCE. Results Mean preoperative, postoperative, and delayed PCE were 21.0 mL (SD 15.5), 18.6 mL (SD 11.4), and 18.4 mL (SD 15.5), respectively. The percentage of ICH evacuated correlated significantly with a decrease in postoperative PCE (r=−0.46, p<0.01). Linear regression analysis revealed a significant relation between preoperative hematoma volume and both postoperative PCE (p<0.001) and postoperative relative PCE (p<0.001). The mean peak PCE was 26.4 mL (SD 15.6) and occurred at 6.5 days (SD 4.8) post-ictus. The 2-week postoperative time course of relative PCE did not fluctuate, suggesting stability in edema during the perioperative period surrounding evacuation and up to 2 weeks after the initial bleed. Conclusions We present a detailed and accurate method for measuring PCE volume with semi-automatic, threshold-guided segmentation software in the postoperative patient with ICH. Decrease in PCE after MIS evacuation correlated with evacuation percentage, and relative PCE remained stable after minimally invasive endoscopic ICH evacuation.
Effects of emotional cues on novel word learning in typically developing children in relation to broader autism traits

Abstract Emotion can influence various cognitive processes. Communication with children often involves exaggerated emotional expressions and emotive language. Children with autism spectrum disorder often show a reduced tendency to attend to emotional information. Typically developing children aged 7 to 9 years who varied in their level of autism-like traits learned the nonsense word names of nine novel toys, which were presented with either happy, fearful, or neutral emotional cues. Emotional cues had no influence on word recognition or recall performance. Eye-tracking data showed differences in visual attention depending on the type of emotional cues and level of autism-like traits. The findings suggest that the influence of emotion on attention during word learning differs according to whether the children have lower or higher levels of autism-like traits, but this influence does not affect word learning outcomes.
Functional foods and bioactive ingredients harnessed from the ocean: current status and future perspectives

Abstract With an increase in life expectancy and decrease of quality-of-life couple with the high prevalence of diseases, diet is expected to play a key function in sustaining human health. Nutritionists, food technologists and medical experts are working in synergy to cater for the increasing demand of food with associated therapeutic benefits, commonly known as functional food, that may improve well-being and reduce the risk of diseases. Interestingly, the marine ecosystem, due to its abundant and phenomenal biodiversity of marine organisms, constitutes a vital source of a panoply of healthy foods supply for the thriving functional food industry. Marine organisms such as seaweeds, sea cucumbers, sponges, and mollusks amongst others are sources of thousands of biologically active metabolites with antioxidant, anti-parasitic, antiviral, anti-inflammatory and anticancer properties. Given the growing number of research and interest to probe into the therapeutic roles of marine products, this review was designed to provide a comprehensive summary of the therapeutic properties of marine organisms (macroalgae, sea cucumbers and fish among others) which are consumed worldwide, in addition to their potentials and as sources of functional ingredients for developing novel food and fostering wellness. The gap between research development and actual commercialization, and future prospects of marine-based products also summarized to some extent. Graphical Abstract
Human Touch Receptors Are Sensitive to Spatial Details on the Scale of Single Fingerprint Ridges

Fast-adapting type 1 (FA-1) and slowly-adapting type 1 (SA-1) first-order tactile neurons provide detailed spatiotemporal tactile information when we touch objects with fingertips. The distal axon of these neuron types branches in the skin and innervates many receptor organs associated with fingerprint ridges (Meissner corpuscles and Merkel cell neurite complexes, respectively), resulting in heterogeneous receptive fields whose sensitivity topography includes many highly sensitive zones or “subfields. ” In experiments on humans of both sexes, using raised dots that tangentially scanned the receptive field we examined the spatial acuity of the subfields of FA-1 and SA-1 neurons and its constancy across scanning speed and direction. We report that the sensitivity of the subfield arrangement for both neuron types on average corresponds to a spatial period of ∼0.4 mm and provide evidence that a subfield's spatial selectivity arises because its associated receptor organ measures mechanical events limited to a single papillary ridge. Accordingly, the sensitivity topography of a neuron's receptive fields is quite stable over repeated mappings and over scanning speeds representative of real-world hand use. The sensitivity topography is substantially conserved also for different scanning directions, but the subfields can be relatively displaced by direction-dependent shear deformations of the skin surface. SIGNIFICANCE STATEMENT The branching of the distal axon of human first-order tactile neurons with receptor organs associated with fingerprint ridges (Meissner and Merkel end-organs) results in cutaneous receptive fields composed of several distinct subfields spread across multiple ridges. We show that the subfields' spatial selectivity typically corresponds to the dimension of the ridges (∼0.4 mm) and a neuron's subfield layout is well preserved across tangential movement speeds and directions representative of natural use of the fingertips. We submit that the receptor organs underlying subfields essentially measure mechanical events at individual ridges. That neurons receive convergent input from multiple subfields does not preclude the possibility that spatial details can be resolved on the scale of single fingerprint ridges by a population code.
Early-Onset Parkinsonism and Early-Onset Parkinson's Disease: A Population-Based Study (2010-2015).

BACKGROUND Early-onset Parkinson's disease (EOPD), occurring between ages 40 and 55, carries social, societal, and personal consequences and may progress, with fewer comorbidities than typical, later-onset disease. OBJECTIVE To examine the incidence and survival of EOPD and other Parkinsonism occurring before age 55 in the population-based cohort of residents in seven Minnesota counties. METHODS A movement-disorder specialist reviewed all the medical records in a 2010-2015 Parkinsonism-incident cohort to confirm diagnosis and subtypes. RESULTS We identified 27 patients diagnosed at < 50 years with incident Parkinsonism 2010-15:11 (41%) cases of EOPD, 13 (48%) drug-induced Parkinsonism, and 3 (11%) other Parkinsonism and 69 incident cases of Parkinsonism < 55 years of age. Overall incidence for Parkinsonism < 50 years was 1.98/100,000 person-years, and for EOPD was 0.81/100,000 person-years. In patients < 55 years, Parkinsonism incidence was 5.05/100,000 person-years: in EOPD, 2.05/100,000 person-years. Levodopa-induced dyskinesia was present in 45%of EOPD (both < 50 years and < 55 years). Onset of cardinal motor symptoms was proximate to the diagnosis of EOPD, except for impaired postural reflexes, which occurred later in the course of EOPD. Among the 69 Parkinsonism cases < 55 years, 9 (13%; all male) were deceased (only 1 case of EOPD). Men had a higher mortality risk compared to women (p = 0.049). CONCLUSION The incidence of EOPD < 50 years was 0.81/100,000 person-years (1.98 in Parkinsonism all type); prior to 55 years was 2.05/100,000 person-years (5.05 in Parkinsonism all type) with higher incidence in men than women. Men with Parkinsonism, all type, had higher mortality compared to women.
Associations Between Pornography Use Frequency, Pornography Use Motivations, and Sexual Wellbeing in Couples

ABSTRACT Pornography use is prevalent, even among partnered individuals. Although pornography use motivations represent key predictors of sexual behaviors, prior studies only assessed the associations between pornography use frequency and sexual wellbeing, with mixed results. This cross-sectional dyadic study examined the associations between partners’ individual and partnered pornography use frequency, motivations, and sexual wellbeing. Self-report data from 265 couples (Mage_men = 31.49 years, SD = 8.26; Mage_women = 29.36 years, SD = 6.74) were analyzed using an actor-partner interdependence model. Men’s greater emotional avoidance motivation was related to their own lower sexual function (β = −.24, p = .004) and greater sexual distress (β = .19, p = .012), while their higher sexual curiosity motivation was related to higher partnered sexual frequency (β = .15, p = .031), their own greater sexual satisfaction (β = .13, p = .022), sexual function (β = .16, p = .009), and lower sexual distress (β = −.13, p = .043). Women’s higher partnered pornography use frequency was associated with their own greater sexual function (β = .15, p = .034) and lower sexual distress (β = −.14, p = .012). Additionally, women’s higher individual pornography use frequency (β = .33, p < .001) and lower sexual pleasure motivation (β = −.35, p = .002) were associated with higher partnered sexual frequency. No partner effects were observed. Findings highlight that women’s pornography use frequency and each partner’s motivations might play crucial roles in couples’ sexual wellbeing.