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Genetic variation accounts for much of the risk for developing a substance use disorder (SUD). Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine intravenous self-administration (IVSA). Computational genetic analysis of IVSA data obtained from an inbred strain panel identifiedNav1,a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this hypothesis, we generated and characterizedNav1knockout (KO) mice.Nav1KO mice exhibited increased cocaine intake during IVSA testing. Surprisingly,Nav1KO mice also displayed a reduced susceptibility to become opioid dependent or develop opioid-induced hyperalgesia after chronic morphine administration, and had impaired spatial learning/memory. Immunohistochemistry and electrophysiology studies revealed that inhibitory synapse density in the cortex ofNav1KO mice was reduced, and excitatory synaptic transmission was increased in theNav1KO cortex and hippocampus. Transcriptomic analysis revealed thatNav1KO mice had a marked increase in excitatory neurons in a deep cortical layer. Collectively, our results indicate thatNav1regulates learning, memory, and the response to multiple addictive drugs, and that changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus could possibly mediate these phenotypic effects.

Owning ambitiousness madaris were reputable in history. Where the complicated questions of Greek philosophy were answered in this assumption that never raised again and new group of Ulamah was formed in holistic Islamic outline. Whole development of Islamic world was happened due to these Madaris. The change of time was as transformed so Madaris could not preserve their steps with age. By comparison of this teaching to time, it seems true to say that the teaching of Madaris is such fossil that the coffle of people’s intellect had crossed it more than hundred years ago. The directions of era and Madris were totally changed whereas the adaptation was dire need through Islamisation of knowledge. To have a same pace of era, minimum some special subjects of sciences are essential to be annexed within Islamic perspective, in the curriculum of Madaris. It is prerequisite to diametrically change their priorities, Madrais should come on the agreement from internal disagreements. To restoring their historical traditions Madaris should prove, that the Holy Quran is the main source of all type of knowledge.

For yeast cells, tolerance to high levels of ethanol is vital both in their natural environment and in industrially relevant conditions. We recently genotyped experimentally evolved yeast strains adapted to high levels of ethanol and identified mutations linked to ethanol tolerance. In this study, by integrating genomic sequencing data with quantitative proteomics profiles from six evolved strains (data set identifier PXD006631) and construction of protein interaction networks, we elucidate exactly how the genotype and phenotype are related at the molecular level. Our multi-omics approach points to the rewiring of numerous metabolic pathways affected by genomic and proteomic level changes, from energy-producing and lipid pathways to differential regulation of transposons and proteins involved in cell cycle progression. One of the key differences is found in the energy-producing metabolism, where the ancestral yeast strain responds to ethanol by switching to respiration and employing the mitochondrial electron transport chain. In contrast, the ethanol-adapted strains appear to have returned back to energy production mainly via glycolysis and ethanol fermentation, as supported by genomic and proteomic level changes. This work is relevant for synthetic biology where systems need to function under stressful conditions, as well as for industry and in cancer biology, where it is important to understand how the genotype relates to the phenotype. ispartof: JOURNAL OF PROTEOME RESEARCH vol:20 issue:8 pages:3840-3852 ispartof: location:United States status: published

Background & aims Since human induced pluripotent stem cells (iPSCs) develop into hepatic organoids through stages that resemble human embryonic liver development, they can be used to study developmental processes and disease pathology. Therefore, we examined the early stages of hepatic organoid formation to identify key pathways affecting early liver development. Methods Single-cell RNA-sequencing and metabolomic analysis was performed on developing organoid cultures at the iPSC, hepatoblast (day 9) and mature organoid stage. The importance of the phosphatidylethanolamine biosynthesis pathway to early liver development was examined in developing organoid cultures using iPSC with a CRISPR-mediated gene knockout and an over the counter medication (meclizine) that inhibits the rate-limiting enzyme in this pathway. Meclizine's effect on the growth of a human hepatocarcinoma cell line in a xenotransplantation model and on the growth of acute myeloid leukemia cells in vitro was also examined. Results Transcriptomic and metabolomic analysis of organoid development indicated that the phosphatidylethanolamine biosynthesis pathway is essential for early liver development. Unexpectedly, early hepatoblasts were selectively sensitive to the cytotoxic effect of meclizine. We demonstrate that meclizine could be repurposed for use in a new synergistic combination therapy for primary liver cancer: a glycolysis inhibitor reprograms cancer cell metabolism to make it susceptible to the cytotoxic effect of meclizine. This combination inhibited the growth of a human liver carcinoma cell line in vitro and in a xenotransplantation model, without causing significant side effects. This drug combination was also highly active against acute myeloid leukemia cells. Conclusion Our data indicate that phosphatidylethanolamine biosynthesis is a targetable pathway for cancer; meclizine may have clinical efficacy as a repurposed anti-cancer drug when used as part of a new combination therapy. Lay summary The early stages of human liver development were modeled using human hepatic organoids. We identified a pathway that was essential for early liver development. Based upon this finding, a novel combination drug therapy was identified that could be used to treat primary liver cancer and possibly other types of cancer.

Deceased donor kidney transplants represent an important source of renal replacement for the 100 000 patients initiating hemodialysis annually. We compared the association of induction therapy, anti-thymocyte globulin [rabbit] (rATG) or basiliximab, with posttransplant rejection, graft and patient survival.Using the United Network for Organ Sharing (UNOS) database, we identified patients that received deceased donor kidney transplants. The outcomes analyzed were 6- month rejection, 1-year rejection, patient survival and graft survival. Multivariate logistic regression models were constructed to understand the association of induction therapy and rejection. Cox-proportional hazards models were constructed to ascertain the association of choice of induction therapy with both patient and graft survival.Of 45 339 patients, 33 906 patients received rATG induction therapy and 11 433 patients received basiliximab induction therapy. The rATG group were younger (53.44 years vs 55.28 years, P 0.001), more frequently female (58.74% male vs 66.08%, P 0.001) and more frequently Black (34.78% vs 25.66%, p 0.001) compared with patients in the basiliximab group. Rejection was more likely with basiliximab compared with rATG at 6 months(OR = 1.64, P 0.001; 7.81% Basiliximab vs 5.23% rATG)and at 12 months (OR = 1.56, P 0.001; 8.81% Basiliximab vs 6.31% rATG). Basiliximab induction therapy was associated with worse patient survival, (HR = 1.05, P = 0.017). Basiliximab induction therapy was associated with worse graft survival, (HR = 1.03, P = 0.037).The analysis of the national experience demonstrated favorable rejection, patient survival, and graft survival with rATG usage. Further prospective data are necessary to provide treatment recommendations.

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.