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Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.

Benzodipyrrole-2,6-dione-3,7-diylidenedimalononitriles (BDPMs) were synthesized as active materials for the use in air-stable n-type organic field-effect transistors (OFETs), whose optical and elec...

In this study, we establish a population-based human induced pluripotent stem cell (hiPSC) drug screening platform for toxicity assessment. After recruiting 1,000 healthy donors and screening for high-frequency human leukocyte antigen (HLA) haplotypes, we identify 13 HLA-homozygous "super donors" to represent the population. These "super donors" are also expected to represent at least 477,611,135 of the global population. By differentiating these representative hiPSCs into cardiomyocytes and neurons we show their utility in a high-throughput toxicity screen. To validate hit compounds, we demonstrate dose-dependent toxicity of the hit compounds and assess functional modulation. We also show reproducible in vivo drug toxicity results using mouse models with select hit compounds. This study shows the feasibility of using a population-based hiPSC drug screening platform to assess cytotoxicity, which can be used as an innovative tool to study inter-population differences in drug toxicity and adverse drug reactions in drug discovery applications.

Leucine rich repeat kinase (LRRK2) is the most prevalent genetic cause for Parkinson's disease. LRRK2 p.G2385R is an Asian specific genetic risk factor for sporadic Parkinson's disease. We generated two induced pluripotent stem cells (iPSCs), IBMS-iPSC-018-09 and IBMS-iPSC-020-01, from the peripheral blood mononuclear cells of two patients carrying LRRK2 p.G2385R variant by using the Sendai-virus delivery system. These iPSCs had a normal karyotype and exhibited pluripotency, such as an embryonic stem cell-like morphology, expression of pluripotent markers, and capacity to differentiate into three germ layers. This cellular model will provide a platform for pathophysiological studies of neurodegeneration in Parkinson's disease.

Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome results from an A to G transition at nucleotide position 8344 in the tRNALys gene of mitochondrial DNA (mtDNA) and is characterized by myoclonus, myopathy and severe neurological symptoms. In this study, Sendai reprogramming method was used to generate an iPS cell line carrying the A8344G mutation of mtDNA from a MERRF patient. This patient-specific iPSC line expressed pluripotent stem cell markers, possessed normal karyotype, and displayed the capability to differentiate into mature cells in three germ layers.

Sensorineural hearing loss (SNHL) is a prevalent form of deafness commonly arising from damage to the cochlear sensory hair cells and degeneration of the spiral ganglion neurons. In this study, Sendai virus was used to generate an induced pluripotent stem cell (iPSC) line from a 39-year-old female patient diagnosed with severe-to-profound, non-syndromic SNHL. The patient also carries a A1555G mutation in the mitochondrial 12S ribosome RNA gene (MTRNR1). This iPSC line was verified to express pluripotent markers, possess normal karyotype, harbor the specific mutation and demonstrated the capacity to differentiate into three germ layers.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited forms of polycystic kidney disease, and is characterized by the growth of numerous cysts in both kidneys. Here we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a 63-year-old female ADPKD patient carrying an R803X mutation in the PKD2 gene using the Sendai-virus delivery system. Downstream characterization of these iPSCs showed that they possessed normal karyotyping, were free of genomic integration, retained the disease-causing PKD2 mutation, expressed pluripotency markers and could differentiate into three germ layers.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by interactions between genetic and environmental factors. Leucine rich repeat kinase (LRRK2) is the most prevalent mutation in autosomal-dominant inheritance of PD. Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a female patient with p.I2012T mutation in LRRK2 gene by using the Sendai-virus delivery system. The resulting iPSCs had a normal karyotype. The iPSCs also showed pluripotency confirmed by immunofluorescent staining and differentiated into the 3 germ layers in vivo. This cellular model will provide a useful platform for further pathophysiological studies of PD.

Autosomal dominant polycystic kidney disease is one of the most prevalent forms of inherited cystic kidney disease, and can be characterized by kidney cyst formation and enlargement. Here we report the generation of a Type 1 ADPKD disease iPS cell line, IBMS-iPSC-012-12, which retains the conserved deletion of PKD1, normal karyotype and exhibits the properties of pluripotent stem cells such as ES-like morphology, expression of pluripotent markers and capacity to differentiate into all three germ layers. Our results show that we have successfully generated a patient-specific iPS cell line with a mutation in PKD1 for study of renal disease pathophysiology.

Benzodipyrrole-2,6-dione-3,7-diylidenedimalononitriles (BDPMs) were synthesized as active materials for the use in air-stable

The synthesis, characterization, and application of two angular-shaped naphthalene bis(1,5-diamide-2,6-diylidene)malononitriles (NBAMs) as high-performance air-stable n-type organic field effect transistor (OFET) materials are reported. NBAM derivatives exhibit deep lowest-unoccupied molecular orbital (LUMO) levels, suitable for air-stable n-type OFETs. The OFET device based on NBAM-EH fabricated by vapor deposition exhibits a maximum electron mobility of 0.63 cm2 V–1 s–1 in air with an on/off current ratio (Ion/Ioff) of 105.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent monogenic kidney disorder leading to kidney failure. We generated induced pluripotent stem cells (iPSCs) from a 37-year-old man carrying a PKD1 Q533X mutation who suffered from kidney failure and a myocardial infarction. The iPSCs were reprogrammed from the patient's peripheral blood mononuclear cells using the Sendai virus system, and were confirmed to possess the specific PKD1 Q533X mutation and normal karyotype. Pluripotency was confirmed using in vitro and in vivo assays. This iPSC line will be useful for studying the mechanisms driving the complicated pathophysiology of ADPKD.

Currently, mortality compost is managed by temperature as extent of tissue degradation is difficult to assess. In the present study, field-scale mortality compost was constructed with composted brain tissue (Brain) and compost adjacent to brain tissue (CAB) sampled over 230 d. Following genomic DNA extraction, bovine-specific mitochondrial DNA (Mt-DNA) and bacterial 16S rDNA fragments were quantified using real-time PCR. Genomic DNA yield of Brain and CAB decreased rapidly (89-98%) and stabilized after 7 d. Compared to d 0, Brain Mt-DNA rapidly decreased (84-91% reduction on d 7). In CAB, Mt-DNA dramatically increased until d 28 (up to 34,500 times) thereafter decreasing by 77-93% on d 112. Quantification of bovine Mt-DNA indicates tissue degradation was initially characterized by rapid decomposition and release of cell contents into surrounding compost matrix followed by further degradation of Mt-DNA by flourishing microorganisms. Consequently, bovine Mt-DNA copies in compost matrix were reliable indicators of tissue degradation.

The study of springback analysis of 440MPa high strength steel is investigated in this paper. Because of the springback phenomenon is related to the material properties and the deformation mechanism during the forming process, the material properties of 440MPa high strength steel are studied at first. The material properties of 440MPa high strength steel are obtained by conducting cyclic uniaxial tension-compression tests with different strain ranges. In order to apply the material properties obtained from the experiments to the finite element analysis, the material constants required in the Yoshida-Uemori model (Y-U model) with the Bauschinger effect considered are established. For realizing the springback characteristics of 440MPa high strength steel, the U-hat draw-bending and V-shape bending are examined by the finite element analysis. From the simulation results, it finds that the side wall curl phenomenon occurs in the U-hat drawbending and the springback phenomenon appears in the V-shape bending. Moreover, it also shows that the side wall curl phenomenon and springback phenomenon are more obvious in the finite element simulations with the Bauschinger effect considered. Finally, the validation of springback prediction is performed by stamping an engine hood reinforcement with 440MPa high strength steel sheet. From the stamping results, it shows that the simulation results of springback prediction are in a well agreement to the production part data. It also finds that the springback predictions are more accurate by the finite element simulations with the use of the Y-U model. It is also found that for a stamping part which is subjected to a reversed tension-compression deformation in the forming process, the occurrence of the Bauschinger effect is obvious. It is also concluded that the accuracy of springback prediction can be much improved by the use of material model with the Bauschinger effect considered.

Background Mannheimia haemolytica is a commensal bacterium that resides in the upper respiratory tract of cattle that can play a role in bovine respiratory disease. Prophages are common in the M. haemolytica genome and contribute significantly to host diversity. The objective of this research was to undertake comparative genomic analysis of phages induced from strains of M. haemolytica serotype A1 (535A and 2256A), A2 (587A and 1127A) and A6 (1152A and 3927A). Results Overall, four P2-like (535AP1, 587AP1, 1127AP1 and 2256AP1; genomes: 34.9–35.7 kb; G+C content: 41.5–42.1 %; genes: 51–53 coding sequences, CDSs), four λ-like (535AP2, 587AP2, 1152AP2 and 3927AP1; genomes: 48.6–52.1 kb; 41.1–41.4 % mol G+C; genes: 77–83 CDSs and 2 tRNAs) and one Mu-like (3927AP2; genome: 33.8 kb; 43.1 % mol G+C; encoding 50 CDSs) phages were identified. All P2-like phages are collinear with the temperate phage φMhaA1-PHL101 with 535AP1, 2256AP1 and 1152AP1 being most closely related, followed by 587AP1 and 1127AP1. Lambdoid phages are not collinear with any other known λ-type phages, with 587AP2 being distinct from 535AP2, 3927AP1 and 1152AP2. All λ-like phages contain genes encoding a toxin-antitoxin (TA) system and cell-associated haemolysin XhlA. The Mu-like phage induced from 3927A is closely related to the phage remnant φMhaMu2 from M. haemolytica PHL21, with similar Mu-like phages existing in the genomes of M. haemolytica 535A and 587A. Conclusions This is among the first reports of both λ- and Mu-type phages being induced from M. haemolytica. Compared to phages induced from commensal strains of M. haemolytica serotype A2, those induced from the more virulent A1 and A6 serotypes are more closely related. Moreover, when P2-, λ- and Mu-like phages co-existed in the M. haemolytica genome, only P2- and λ-like phages were detected upon induction, suggesting that Mu-type phages may be more resistant to induction. Toxin-antitoxin gene cassettes in λ-like phages may contribute to their genomic persistence or the establishment of persister subpopulations of M. haemolytica. Further work is required to determine if the cell-associated haemolysin XhlA encoded by λ-like phages contributes to the pathogenicity and ecological fitness of M. haemolytica. Electronic supplementary material The online version of this article (doi:10.1186/s12866-015-0494-5) contains supplementary material, which is available to authorized users.