Miracle-dz/UniFAR-FTUs huggingface dataset:
Advanced paternal age effect on offspring's reading ability: The mediating role of thalamic maturation

While advanced paternal age (APA) has repeatedly been associated with a higher risk for neuropsychiatric disorders, its effects on cognitive processes such as reading have received minimal attention. Therefore, we examined the relationship between APA, offspring9s reading abilities, and brain measures in a longitudinal neuroimaging study following 51 children from kindergarten through third grade. APA significantly predicted reduced reading performance, independent of parental reading history, socioeconomic status, home literacy environment, and birth order. This effect was mediated by gray matter volume change in the left posterior thalamus, predominantly the pulvinar nuclei. Complementary analyses using diffusion imaging data, Neurosynth, and 1000 Functional Connectome data indicated the APA-related cluster links to the dorsal attention network. These findings provide novel insights into the neurocognitive mechanisms underlying APA effect on reading during its earliest phase of reading acquisition and suggest future avenues of research on APA-related factors, such as de novo mutation, in reading.
Massively parallel quantification of CRISPR editing in cells by TRAP-seq enables better design of Cas9, ABE, CBE gRNAs of high efficiency and accuracy

The CRISPR RNA-guided endonucleases Cas9, and Cas9-derived adenine/cytosine base editors (ABE/CBE), have been used in both research and therapeutic applications. However, broader use of this gene editing toolbox is hampered by the great variability of efficiency among different target sites. Here we present TRAP-seq, a versatile and scalable approach in which the CRISPR gRNA expression cassette and the corresponding surrogate site are captured by Targeted Reporter Anchored Positional Sequencing in cells. TRAP-seq can faithfully recapitulate the CRISPR gene editing outcomes introduced to the corresponding endogenous genome site and most importantly enables massively parallel quantification of CRISPR gene editing in cells. We demonstrate the utility of this technology for high-throughput quantification of SpCas9 editing efficiency and indel outcomes for 12,000 gRNAs in human embryonic kidney cells. Using this approach, we also showed that TRAP-seq enables high throughput quantification of both ABE and CBE efficiency at 12,000 sites in cells. This rich amount of ABE/CBE outcome data enable us to reveal several novel nucleotide features (e.g. preference of flanking bases, nucleotide motifs, STOP recoding types) affecting base editing efficiency, as well as designing improved machine learning-based prediction tools for designing SpCas9, ABE and CBE gRNAs of high efficiency and accuracy (>70%). We have integrated all the 12,000 CRISPR gene editing outcomes for SpCas9, ABE and CBE into a CRISPR-centered portal: The Human CRISPR Atlas. This study extends our knowledge on CRISPR gene and base editing, and will facilitate the application and development of CRISPR in both research and therapy.
Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ∼200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three “immunotypes” associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.
Developing a Fully-glycosylated Full-length SARS-CoV-2 Spike Protein Model in a Viral Membrane

This technical study describes all-atom modeling and simulation of a fully-glycosylated fulllength SARS-CoV-2 spike (S) protein in a viral membrane. First, starting from PDB:6VSB and 6VXX, full-length S protein structures were modeled using template-based modeling, de-novo protein structure prediction, and loop modeling techniques in GALAXY modeling suite. Then, using the recently-determined most occupied glycoforms, 22 N-glycans and 1 O-glycan of each monomer were modeled using Glycan Reader & Modeler in CHARMM-GUI. These fully-glycosylated full-length S protein model structures were assessed and further refined against the low-resolution data in their respective experimental maps using ISOLDE. We then used CHARMM-GUI Membrane Builder to place the S proteins in a viral membrane and performed all-atom molecular dynamics simulations. All structures are available in CHARMM-GUI COVID-19 Archive (http://www.charmm-gui.org/docs/archive/covid19), so researchers can use these models to carry out innovative and novel modeling and simulation research for the prevention and treatment of COVID-19.
Oxidative stress and neuroinflammation in a rat model of co-morbid obesity and psychogenic stress

Background There is growing recognition for a reciprocal, bidirectional link between anxiety disorders and obesity. Although the mechanisms linking obesity and anxiety remain speculative, this bidirectionality suggests shared pathophysiological processes. Neuroinflammation and oxidative damage are implicated in both pathological anxiety and obesity. This study investigates the relative contribution of comorbid diet-induced obesity and stress-induced anxiety to neuroinflammation and oxidative stress. Methods Thirty-six (36) male Lewis rats were divided into four groups based on diet type and stress exposure: 1) control diet unexposed (CDU) and 2) exposed (CDE), 3) Western-like high-saturated fat diet unexposed (WDU) and 4) exposed (WDE). Neurobehavioral tests were performed to assess anxiety-like behaviors. The catalytic concentrations of glutathione peroxidase and reductase were measured from plasma samples, and neuroinflammatory/oxidative stress biomarkers were measured from brain samples using Western blot. Correlations between behavioral phenotypes and biomarkers were assessed with Pearson’s correlation procedures. Results We found that WDE rats exhibited markedly increased levels of glial fibrillary acidic protein (185%), catalase protein (215%), and glutathione reductase (GSR) enzymatic activity (418%) relative to CDU rats. Interestingly, the brain protein levels of glutathione peroxidase (GPx) and catalase were positively associated with body weight and behavioral indices of anxiety. Conclusions Together, our results support a role for neuroinflammation and oxidative stress in heightened emotional reactivity to obesogenic environments and psychogenic stress. Uncovering adaptive responses to obesogenic environments characterized by high access to high-saturated fat/high-sugar diets and toxic stress has the potential to strongly impact how we treat psychiatric disorders in at-risk populations. Highlights Predatory odor stress heightens footshock reactivity and anxiety-like behaviors in Lewis rats. WD intake increases glutathione reductase activity in plasma. WD intake and PS exposure acted synergistically to increase the brain protein levels of catalase and the glial fibrillary acidic protein. The protein levels and activities of some redox/neuroinflammatory biomarkers are closely associated with behavioral proxies related to fear and anxiety in rats.
Chromosome-level reference genome of the European wasp spider Argiope bruennichi: a resource for studies on range expansion and evolutionary adaptation

Background Argiope bruennichi, the European wasp spider, has been studied intensively as to sexual selection, chemical communication, and the dynamics of rapid range expansion at a behavioral and genetic level. However, the lack of a reference genome has limited insights into the genetic basis for these phenomena. Therefore, we assembled a high-quality chromosome-level reference genome of the European wasp spider as a tool for more in-depth future studies. Findings We generated, de novo, a 1.67Gb genome assembly of A. bruennichi using 21.5X PacBio sequencing, polished with 30X Illumina paired-end sequencing data, and proximity ligation (Hi-C) based scaffolding. This resulted in an N50 scaffold size of 124Mb and an N50 contig size of 288kb. We found 98.4% of the genome to be contained in 13 scaffolds, fitting the expected number of chromosomes (n = 13). Analyses showed the presence of 91.1% of complete arthropod BUSCOs, indicating a high quality of the assembly. Conclusions We present the first chromosome-level genome assembly in the class Arachnida. With this genomic resource, we open the door for more precise and informative studies on evolution and adaptation in A. bruennichi, as well as on several interesting topics in Arachnids, such as the genomic architecture of traits, whole genome duplication and the genomic mechanisms behind silk and venom evolution.
Chromosome numbers of Diospyros kaki cultivars

The chromosome numbers in 18 cultivars and 94 open-pollinated progenies from 14 Cultivars of D. kaki were investigated by the method of enzymatic maceration or squash method, using shoot apical meristem tissue and root tips. The improved techniques made chromosomes able to be well-counted, especially when treated by enzymatic maceration. Chromosome numbers of 2n= 135 were observed in `Hiratanenashi' and `Tone Wase', which was derived from `Hiratanenashi' by bud mutation. As had already been reported, the basic chromosome number of Diospyros plants is 15, so these cultivars would be 2n = 9x, and it suggested that polyploidy had occurred in D. kaki. However, no change was recognized in chromosme numbers of the other 16 cultivars and 94 openpollinated progenies from 14 cultivars.
Evidence for Dosage Compensation in Coccinia grandis, a Plant with a Highly Heteromorphic XY System

Some ~15.000 angiosperms are dioecious, but mechanisms of sex determination in plants remain poorly understood. In particular, how Y chromosomes evolve and degenerate, and whether dosage compensation evolves as a response, are matters of debate. Here we focus on Coccinia grandis, a dioecious cucurbit with the highest level of X/Y heteromorphy recorded so far. We identified sex-linked genes using RNA sequences from a cross and a model-based method termed SEX-DETector. Parents and F1 individuals were genotyped and the transmission patterns of SNPs then analysed. In the >1300 sex-linked genes studied, X-Y divergence was 0.13 - 0.17, and substantial Y degeneration is implied by an average Y/X expression ratio of 0.63 and an inferred gene loss on the Y of ~40%. We also found reduced Y gene expression being compensated by elevated expression of corresponding genes on the X and an excess of sex-biased genes on the sex chromosomes. Molecular evolution of sex-linked genes in C. grandis is thus comparable to that in Silene latifolia, another dioecious plant with a strongly heteromorphic XY system, and cucurbits are the fourth plant family in which dosage compensation is described, suggesting it might be common in plants.
On the effectiveness of small, discriminatively pre-trained language representation models for biomedical text mining

Neural language representation models such as BERT [1] have recently shown state of the art performance in downstream NLP tasks and bio-medical domain adaptation of BERT (Bio-BERT [2]) has shown same behavior on biomedical text mining tasks. However, due to their large model size and resulting increased computational need, practical application of models such as BERT is challenging making smaller models with comparable performance desirable for real word applications. Recently, a new language transformers based language representation model named ELECTRA [3] is introduced, that makes efficient usage of training data in a generative-discriminative neural model setting that shows performance gains over BERT. These gains are especially impressive for smaller models. Here, we introduce a small ELECTRA based model named Bio-ELECTRA that is eight times smaller than BERT BASE and achieves comparable performance on biomedical question answering and yes/no question answer classification tasks. The model is pre-trained from scratch on PubMed abstracts using a consumer grade GPU with only 8GB memory. For biomedical named entity recognition, however, large BERT Base model outperforms both Bio-ELECTRA and ELECTRA-Small++.
Does K-line (-) in the Neck-flexed Position Predict Surgical Outcome of Cervical Spondylotic Myelopathy? Results of a Multivariate Analysis After Muscle-Preserving Selective Laminectomy.

STUDY DESIGN A retrospective single-center study. OBJECTIVE To investigate the influence of the K-line in the neck-flexed position (flexion K-line) on the surgical outcome after muscle-preserving selective laminectomy (SL) for cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA Development of CSM is associated with dynamic factors and cervical alignment. The flexion K-line, which reflects both dynamic and alignment factors, provides an indicator of surgical outcome after posterior decompression surgery for patients with ossification of the posterior longitudinal ligament. However, the value of the flexion K-line for patients with CSM has not been evaluated. METHODS Our study group included 159 patients treated with SL for CSM. Patients were divided into a flexion K-line (+) group and a flexion K-line (-) group. The influence of the flexion K-line on radiological and surgical outcomes was analyzed, with multivariate analysis conducted to identify factors affecting the surgical outcome. RESULTS Patients in the flexion K-line (-) group were younger (P = 0.003), had a less lordotic cervical alignment (pre-and postoperatively, P < 0.001), a smaller C7 slope (pre-and postoperatively, P < 0.001), and a greater mismatch between the C7 slope and the C2-C7 angle (preoperatively, P = 0.047; postoperatively, P = 0.001). The postoperative increase in Japanese Orthopedic Association (JOA) score and the JOA score recovery rate (RR) were lower for the flexion K-line (-) than for the K-line (+) group (P < 0.001 and P < 0.001, respectively). On multivariate regression analysis, the flexion K-line (-) (β= -0.282, P < 0.001), high signal intensity (SI) changes on T2-weighted image (WI) combined with low SI changes on T1-WI in the spinal cord (β= -0.266, P < 0.001), and older age (β= -0.248, P = 0.001) were predictive of a lower JOA score RR. CONCLUSIONS The flexion K-line may be a useful predictor of surgical outcomes after SL in patients with CSM. LEVEL OF EVIDENCE 4.
Successful Treatment of Rituximab-Associated Palmoplantar Pustulosis With Apremilast in a Patient With Seropositive Rheumatoid Arthritis

T he use of biological therapies for the treatment of rheumatoid arthritis (RA) has significantly improved outcomes in patients with an inadequate response to conventional synthetic diseasemodifying antirheumatic drugs. Paradoxically, individual patients may experience worsening of preexisting or new onset of psoriasis, including palmoplantar pustulosis, most often in association with the use of tumor necrosis factor (TNF) inhibitors and less frequently with non-TNF biologics. We here report the case of a 57-year-old woman presenting to our clinic with active rheumatoid factor and anticitrullinated protein antibody–positive RA, diagnosed in 2016. Pretreatment included methotrexate and certolizumab. Under tocilizumab, she developed psoriatic skin lesions. Subsequently, tofacitinib was started but ineffective. Abatacept was initiated, and RA disease activity subsequently improved, but after 5 months, psoriatic skin eruptions were noted, and abatacept was stopped, leading to cutaneous healing. The first course of rituximab (2 infusions of 1000 mg 2 weeks apart) in April 2018 was well tolerated and resulted in a decrease of Disease Activity Score in 28 joints from 6.2 to 3.6. Leflunomide was added at 20 mg/d in August 2018, whereas prednisone was maintained at 10 mg/d. A second course of rituximabwaswell tolerated. In April 2019, the patient received the first infusion of the third rituximab course, but 3 days later, she started to develop palmoplantar pustulosis, which deteriorated over the course of 1 week. Despite immediate treatment with topical steroids and phototherapy, as well as a temporary increase of oral prednisone, the palmoplantar pustular lesions did not improve (Figure, left side). Six weeks after the last rituximab infusion, apremilast was started and increased up to 30 mg twice daily. It was well tolerated, and significant improvement of palmoplantar pustulosis was observed within 6 weeks (Figure, right side). Data from the French AIR registry have questioned a causal association of rituximab and new onset or worsening of preexisting psoriasis, showing incidence ratios similar to the general population. In the German RABBIT registry, the use of rituximab was not associated with a significant increase in new-onset psoriasis in comparison to conventional synthetic disease-modifying antirheumatic drug treatment.
Veno-venous Extracorporeal Membrane Oxygenation for Respiratory Failure in COVID-19 Patients

Summary and Background Data: VV ECMO can be utilized as an advanced therapy in select patients with COVID-19 respiratory failure refractory to traditional critical care management and optimal mechanical ventilation. Anticipating a need for such therapies during the pandemic, our center created a targeted protocol for ECMO therapy in COVID-19 patients that allows us to provide this life-saving therapy to our sickest patients without overburdening already stretched resources or excessively exposing healthcare staff to infection risk. Methods: As a major regional referral program, we used the framework of our well-established ECMO service-line to outline specific team structures, modified patient eligibility criteria, cannulation strategies, and management protocols for the COVID-19 ECMO program. Results: During the first month of the COVID-19 outbreak in Massachusetts, 6 patients were placed on VV ECMO for refractory hypoxemic respiratory failure. The median (interquartile range) age was 47 years (43–53) with most patients being male (83%) and obese (67%). All cannulations were performed at the bedside in the intensive care unit in patients who had undergone a trial of rescue therapies for acute respiratory distress syndrome including lung protective ventilation, paralysis, prone positioning, and inhaled nitric oxide. At the time of this report, 83% (5/6) of the patients are still alive with 1 death on ECMO, attributed to hemorrhagic stroke. 67% of patients (4/6) have been successfully decannulated, including 2 that have been successfully extubated and one who was discharged from the hospital. The median duration of VV ECMO therapy for patients who have been decannulated is 12 days (4–18 days). Conclusions: This is 1 the first case series describing VV ECMO outcomes in COVID-19 patients. Our initial data suggest that VV ECMO can be successfully utilized in appropriately selected COVID-19 patients with advanced respiratory failure.
Effect of Different Amounts of Winter Chilling on Fruitfulness of Several Olive Varieties

1. Inflorescence and subsequent fruit production in eight varieties of olives was, in general, directly proportional to the amount of winter chilling received. Trees of each variety maintained in a warm greenhouse throughout the winter failed to produce a single inflorescence. 2. The number of flowers per inflorescence or the percentage of perfect flowers produced was not affected by the amount of winter chilling 3. The varieties Ascolano and Sevillano required the maximum amount of winter chilling encountered at Davis, California, during each of two winters before appreciable amounts of inflorescences were produced 4. The varieties Mission, Criolla, Barouni, and Manzanillo produced some inflorescences with intermediate amounts of chilling, although considerably more developed with the full amount of chilling 5. In the 1956-57 tests the Rubra and Azapa varieties were able to produce substantial numbers of inflorescences under the minimum amount of chilling given, indicating that they might be adaptable to regions of relatively high winter temperatures.
Clinical significance of clonal hematopoiesis in the interpretation of blood liquid biopsy

As the use of next‐generation sequencing (NGS) for plasma cell‐free DNA (cfDNA) continues to expand in clinical settings, accurate identification of circulating tumor DNA mutations is important to validate its use in the clinical management for cancer patients. Here, we aimed to characterize mutations including clonal hematopoiesis (CH)‐related mutations in plasma cfDNA and tumor tissues using the same ultradeep NGS assay and evaluate the clinical significance of CH‐related mutations on the interpretation of liquid biopsy results. Ultradeep targeted NGS using Oncomine Pan‐Cancer Panel was performed on matched surgically resected tumor tissues, peripheral blood cells (PBCs), and 120 plasma cfDNA samples from 38 colorectal cancer patients. The clinical significance of the CH‐related mutations in plasma cfDNA was evaluated by longitudinal monitoring of the postoperative plasma samples. Among the 38 patients, 74 nonsynonymous mutations were identified from tumor tissues and 64 mutations from the preoperative plasma samples. Eleven (17%) of the 64 mutations identified in plasma cfDNA were also detected in PBC DNA and were identified to be CH‐related mutations. Overall, 11 of 38 (29%) patients in this cohort harbored at least one CH‐related mutation in plasma cfDNA. These CH‐related mutations were continuously detected in subsequent postoperative plasma samples from three patients which could be misinterpreted as the presence of residual disease or as lack of treatment response. Our results indicated that it is essential to integrate the mutational information of PBCs to differentiate tumor‐derived from CH‐related mutations in liquid biopsy analysis. This would prevent the misinterpretation of results to avoid misinformed clinical management for cancer patients.