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In ageing men, benign prostatic hyperplasia (BPH) is a chronic disease that leads to progressive lower urinary tract symptoms (LUTS) caused by obstruction of the bladder outlet (BOO). Patients with LUTS (such as increased frequency and urgency of urination) and complications of BOO (such as hydronephrosis and bladder stones) are at risk of serious health problems. BPH causes a rapidly rising burden of LUTS far exceeding that of other urological conditions. Treatment outcomes are unsatisfactory for BPH largely due to the lacking of fully understanding of the pathogenesis. Hormonal imbalances related to androgen and oestrogen can cause BPH, but the exact mechanism is still unknown, even the animal model is not fully understood. Additionally, there are no large-scale data to explain this mechanism. A BPH mouse model was established using mixed slow-release pellets of testosterone (T) and estradiol (E2), and we measured gene expression in mouse prostate tissue using RNA-seq, verified the results using qRT‒PCR, and used bioinformatics methods to analyse the differentially expressed genes (DEGs).

Background Catheter-related bladder discomfort (CRBD) is a common postoperative bladder pain syndrome. Many drugs and interventions for managing CRBD have been studied, but their comparative effectiveness remains controversial. We made a study to assess the comparative effectiveness of interventions included Ketorolac, Lidocaine, Chlorpheniramine, Gabapentin, Magnesium, Nefopam, Oxycodone, Parecoxib, Solifenacin, Tolterodine, Bupivancaine, Dexmedetomidine, Hyoscine N-butyl bromide, Ketamine, Penile nerve block on urological postoperative CRBD. Methods We performed a network meta-analysis via Aggregate Data Drug Inormation System software included 18 studies with 1816 patients and assessed the risk of bias by Cochrane Collaboration tool. The incidence of moderate to severe CRBD at 0, 1, and 6 h after surgery and the incidence severe CRBD at 1 h after surgery were compared. Result The number of best rank is 0.48(Nefopam) and 0.22(Nefopam) in the incidence of moderate to severe CRBD at 1 h and incidence severe CRBD at 1 h. More than half of studies at unclear or high risk of bias. Conclusion Nefopam reduced the incidence of CRBD and prevented severe events, but limited by the small number of studies for each intervention and heterogeneous patients.

MotivationRoughly 3% of the human genome is composed of variable-number tandem repeats (VNTRs): tandemly repeated arrays of motifs at least six bases. These loci are highly polymorphic: over 61% of insertion and deletion variants at least 50 bases found from long-read assemblies are inside VNTRs. Furthermore, long-read assemblies reveal that VNTR loci are multiallelic, and can vary by both motif composition and copy number. Current approaches that define and merge variants based on alignment breakpoints do not capture this complexity of variation. A natural alternative approach is to instead define the motif composition of VNTR sequences from samples, and to detect differences based on comparisons of repeat composition. However, due to the complexity of VNTR sequences, it is difficult to establish a common reference set of motif sequences that may be used to describe variation in large sequencing studies.ResultsHere we present a method vamos: VNTR Annotation using efficient Motif Sets that for any VNTR locus selects a set of representative motifs from all motifs observed at that locus that may be used to encode VNTR sequences within a bounded edit distance of the original sequence. We use our method to characterize VNTR variation in 32 haplotype-resolved human genomes. In contrast to current studies that merge multi-allelic calls, we estimate an average of 3.1-4.0 alleles per locus.Availabilitygithub.com/chaissonlab/vamos, zenodo.org/record/7158427Contactmchaisso@usc.edu

By introducing functional fillers into the ethylene propylene diene monomer matrix, the anti-ablation, thermal insulation, and adhesive layer were prepared, respectively. We have studied the mechanical properties, ablation properties, thermal insulation properties, and bonding properties of different composite structures after design and analyzed the ceramic mechanism. The results showed that the content of ceramic fillers improved the thermal stability and ablation properties of anti-ablation layer composites. The formation of liquid structure can fill the hole defects and ablation pit. The foaming agent improved thermal insulation properties of the thermal insulation layer, and the strength of the bonding layer has been greatly improved. The design of the composite structure can not only reduce the density but also have an excellent thermal insulation effect. And as the thickness of the heat insulation layer increases, the heat blocking effect becomes more excellent.

Objective The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia. Methods We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. Results RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated. Conclusions We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.

This paper presents the isogeometric least-squares collocation (IGA-L) method, which determines the numerical solution by making the approximate differential operator fit the real differential operator in a least-squares sense. The number of collocation points employed in IGA-L can be larger than that of the unknowns. Theoretical analysis and numerical examples presented in this paper show the superiority of IGA-L over state-of-the-art collocation methods. First, a small increase in the number of collocation points in IGA-L leads to a large improvement in the accuracy of its numerical solution. Second, IGA-L method is more flexible and more stable, because the number of collocation points in IGA-L is variable. Third, IGA-L is convergent in some cases of singular parameterization. Moreover, the consistency and convergence analysis are also developed in this paper.

In October 2020, 62 scientists from nine nations worked together remotely in the Second Baylor College of Medicine & DNAnexus hackathon, focusing on different related topics on Structural Variation, Pan-genomes, and SARS-CoV-2 related research. The overarching focus was to assess the current status of the field and identify the remaining challenges. Furthermore, how to combine the strengths of the different interests to drive research and method development forward. Over the four days, eight groups each designed and developed new open-source methods to improve the identification and analysis of variations among species, including humans and SARS-CoV-2. These included improvements in SV calling, genotyping, annotations and filtering. Together with advancements in benchmarking existing methods. Furthermore, groups focused on the diversity of SARS-CoV-2. Daily discussion summary and methods are available publicly at https://github.com/collaborativebioinformatics provides valuable insights for both participants and the research community.

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent–child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average contig N50: 26 Mbp) integrate all forms of genetic variation across even complex loci such as the major histocompatibility complex. We focus on 107,590 structural variants (SVs), of which 68% are inaccessible by short-read sequencing. We identify new SV hotspots (spanning megabases of gene-rich sequence), characterize 130 of the most active mobile element source elements, and find that 63% of all SVs arise by homology-mediated mechanisms—a twofold increase from previous studies. Our resource now enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1,525 expression quantitative trait loci (SV-eQTLs) as well as SV candidates for adaptive selection within the human population.

MotivationIt is computationally challenging to detect variation by aligning long reads from single-molecule sequencing (SMS) instruments, or megabase-scale contigs from SMS assemblies. One approach to efficiently align long sequences is sparse dynamic programming (SDP), where exact matches are found between the sequence and the genome, and optimal chains of matches are found representing a rough alignment. Sequence variation is more accurately modeled when alignments are scored with a gap penalty that is a convex function of the gap length. Because previous implementations of SDP used a linear-cost gap function that does not accurately model variation, and implementations of alignment that have a convex gap penalty are either inefficient or use heuristics, we developed a method, lra, that uses SDP with a convex-cost gap penalty. We use lra to align long-read sequences from PacBio and Oxford Nanopore (ONT) instruments as well asde novoassembly contigs.ResultsAcross all data types, the runtime of lra is between 52-168% of the state of the art aligner minimap2 when generating SAM alignment, and 9-15% of an alternative method, ngmlr. This alignment approach may be used to provide additional evidence of SV calls in PacBio datasets, and an increase in sensitivity and specificity on ONT data with current SV detection algorithms. The number of calls discovered using pbsv with lra alignments are within 98.3-98.6% of calls made from minimap2 alignments on the same data, and give a nominal 0.2-0.4% increase in F1 score by Truvari analysis. On ONT data with SV called using Sniffles, the number of calls made from lra alignments is 3% greater than minimap2-based calls, and 30% greater than ngmlr based calls, with a 4.6-5.5% increase in Truvari F1 score. When applied to calling variation from de novo assembly contigs, there is a 5.8% increase in SV calls compared to minimap2+paftools, with a 4.3% increase in Truvari F1 score.Availability and implementationAvailable in bioconda:https://anaconda.org/bioconda/lraand github:https://github.com/ChaissonLab/LRAContactmchaisso@usc.edu,jingwenr@usc.edu

Resolving genomic structural variationMany human genomes have been reported using short-read technology, but it is difficult to resolve structural variants (SVs) using these data. These genomes thus lack comprehensive comparisons among individuals and populations. Ebertet al.used long-read structural variation calling across 64 human genomes representing diverse populations and developed new methods for variant discovery. This approach allowed the authors to increase the number of confirmed SVs and to describe the patterns of variation across populations. From this dataset, they identified quantitative trait loci affected by these SVs and determined how they may affect gene expression and potentially explain genome-wide association study hits. This information provides insights into patterns of normal human genetic variation and generates reference genomes that better represent the diversity of our species.Science, this issue p.eabf7117

It is computationally challenging to detect variation by aligning single-molecule sequencing (SMS) reads, or contigs from SMS assemblies. One approach to efficiently align SMS reads is sparse dynamic programming (SDP), where optimal chains of exact matches are found between the sequence and the genome. While straightforward implementations of SDP penalize gaps with a cost that is a linear function of gap length, biological variation is more accurately represented when gap cost is a concave function of gap length. We have developed a method, lra, that uses SDP with a concave-cost gap penalty, and used lra to align long-read sequences from PacBio and Oxford Nanopore (ONT) instruments as well as de novo assembly contigs. This alignment approach increases sensitivity and specificity for SV discovery, particularly for variants above 1kb and when discovering variation from ONT reads, while having runtime that are comparable (1.05-3.76×) to current methods. When applied to calling variation from de novo assembly contigs, there is a 3.2% increase in Truvari F1 score compared to minimap2+htsbox. lra is available in bioconda (https://anaconda.org/bioconda/lra) and github (https://github.com/ChaissonLab/LRA)., Author summary Any two human genomes will have sequence differences across multiple scales: from single-nucleotide variants to large gains, losses, or rearrangements of DNA called structural variants. Long-read single-molecule sequencing has been shown to help discover structural variation because the reads span across the entire variant. The computational problem for discovering a structural variant is to find the optimal alignment of the read to the genome with gaps that accurately reflect the variant. Here we demonstrate a method, lra, that uses an efficient implementation of concave-cost alignment for structural variant discovery using long reads. On standardized benchmark data, we show that structural variant discovery is improved for multiple combinations of variant detection algorithms and long-read sequence using alignments generated by lra compared to existing methods. Finally, we show that it is possible to use lra to accurately discover a complete spectrum of structural variants using de novo assemblies constructed from long-read sequence data. This implies a future model of comparative genomics where variants are discovered only by comparing de novo assemblies and not a comparison of reads against a reference.

During a LOCA accident, the debris caused by the action of high energy fluid discharged from the break may transport to the containment sump, then may be entrained into the core by the ECCS water. The debris may cause the blockage of fuel assembly. The air may also enter the reactor with water. Numerical simulations are performed to analyze the air-water flow and particle-water flow through the blocked fuel assembly. The pressure drop in fuel assembly will impact the long-term core cooling capability. The effects of different parameters on the pressure drop over the fuel assembly are analyzed. Pressure drop increases as blockage percentage, mass flow rate or inlet velocity increases for both two-phase flow. The decrease of air volume fraction and the increase of particle volume fraction all cause the increase of pressure drop. Pressure drop increases slightly as bubble diameter increases, and the tiny effect of particle diameter on pressure drop was found as particle diameter varying at an increment of 10um.

A loss of coolant accident (LOCA) in a PWR (pressurized water reactor) would generate debris from thermal insulation and other materials in the vicinity of the break. It is postulated that debris can transported to the containment sump strainer. Some of the debris may pass through the strainer and could challenge the long-term core cooling capability of the plant. To address this safety issue, the downstream effect tests for the PWR were performed. Sensitivity studies on pressure drops through LOCA-generated debris deposited on a fuel assembly were performed to evaluate the effects of debris type and flow rate. Fibrous debris is the most crucial material in terms of causing pressure drops.

Three new acyl hydrazone compounds C12H12N4O3 (I), C12H14N4O4 (II) and C16H16N4O3 (III) are synthesized and characterized by elemental analysis and single-crystal X-ray diffraction. The crystal structural analyses show that the three compounds crystallize in the monoclinic crystal lattice. Their thermal decomposition processes under nitrogen and air are studied by TG-DTG, the sequence of the thermostability for three compounds at each condition is the same: III > I > II. The interaction modes of the three compounds with CT-DNA are investigated by UV–Vis absorption, showing hyperchromic and hypochromic effects. The thermogenic curves of the three compounds reacting with CT-DNA are measured by microcalorimetry, indicating that they are all endothermic reaction and the reaction times are within 10–30 min.

Sansalvamide A, a cyclic depsipeptide isolated from a marine fungus of the Fusarium genus, exhibits significant antitumor activity. In the present study, H-10 (molecular formula, C38H55N5O6; molecular weight, 677.8732), a novel sansalvamide A derivative, demonstrated an inhibitory effect on the proliferation of murine melanoma B16 cells. It was confirmed that H-10 induced the apoptosis of the B16 cells. The inhibitory rate of various concentrations of H-10 on the B16 cells was measured by sulforhodamine B colorimetric assay, and the results revealed that the inhibitory effect of H-10 on the B16 cells occurred in a concentration-dependent manner. In addition, a growth curve model of the B16 cells treated with 50 μM H-10 revealed that the effect of H-10 also occurred in a time-dependent manner. The apoptotic morphology of the B16 cells was observed using an optical microscope. Following the treatment of the cells with 50 μM H-10 for 24 h, the cell apoptosis rate was analyzed using flow cytometry. The expression levels of caspase-3, -8 and -9 were analyzed by western blot analysis, and the results indicated that H-10 may induce the apoptosis of B16 cells.