Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells

Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-β (IFN-β). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.National Human Genome Research Institute (U.S.) (Grant P50 HG006193)National Institutes of Health (U.S.). Pioneer Award (DP1 CA174427)Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (Grant HG004037)National Institutes of Health (U.S.). Pioneer Award (DP1 MH100706)National Institutes of Health (U.S.) (Transformative R01 Grant R01 DK097768)W. M. Keck FoundationMcKnight FoundationMerkin, Richard N.Damon Runyon Cancer Research FoundationSearle Scholars ProgramSimons Foundatio

Correction: Regev, Y., et al. Molecular Identification and Characterization of Vibrio Species and Mycobacterium Species in Wild and Cultured Marine Fish from the Eastern Mediterranean Sea. Microorganisms 2020, 8, 863

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Long-Term Pain Characteristics and Management Following Minimally Invasive Spinal Decompression and Open Laminectomy and Fusion for Spinal Stenosis

Background and Objectives: To compare the long-term pain characteristics and its chronic management following minimally invasive spinal (MIS) decompression and open laminectomy with fusion for lumbar stenosis. Materials and Methods: The study cohort included patients with a minimum 5-year postoperative follow-up after undergoing either MIS decompression or laminectomy with fusion for spinal claudication. The primary outcome of interest was chronic back and leg pain intensity. Secondary outcome measures included pain frequency during the day, chronic use of non-opioid analgesics, narcotic medications, medical cannabinoids, and continuous interventional pain treatments. Results: A total of 95 patients with lumbar spinal stenosis underwent one- or two-level surgery for lumbar spinal stenosis between April 2009 and July 2013. Of these, 50 patients underwent MIS decompression and 45 patients underwent open laminectomy with instrumented fusion. In the fusion group, a higher percentage of patients experienced moderate-to-severe back pain with 48% compared to 21.8% of patients in the MIS decompression group (p < 0.01). In contrast, we found no significant difference in the reported leg pain in both groups. In the fusion group, 20% of the patients described their back and leg pain as persistent throughout the day compared to only 2.2% in the MIS decompression group (p < 0.05). A trend toward higher chronic dependence on analgesic medication and repetitive pain clinic treatments was found in the fusion group. Conclusions: MIS decompression for the treatment of degenerative spinal stenosis resulted in decreased long-term back pain and similar leg pain outcomes compared to open laminectomy and instrumented fusion surgery

Common genetic variants modulate pathogen-sensing responses in human dendritic cells

Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to E. coli lipopolysaccharide, influenza or interferon-β (IFNβ). We localized and validated causal variants to binding sites of pathogen-activated STAT and IRF transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I interferon induction in response to influenza infection. Our results reveal common alleles that explain inter-individual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases

Exploring the human lacrimal gland using organoids and single-cell sequencing

The lacrimal gland is essential for lubrication and protection of the eye. Disruption of lacrimal fluid production, composition, or release results in dry eye, causing discomfort and damage to the ocular surface. Here, we describe the establishment of long-term 3D organoid culture conditions for mouse and human lacrimal gland. Organoids can be expanded over multiple months and recapitulate morphological and transcriptional features of lacrimal ducts. CRISPR-Cas9-mediated genome editing reveals the master regulator for eye development Pax6 to be required for differentiation of adult lacrimal gland cells. We address cellular heterogeneity of the lacrimal gland by providing a single-cell atlas of human lacrimal gland tissue and organoids. Finally, human lacrimal gland organoids phenocopy the process of tear secretion in response to neurotransmitters and can engraft and produce mature tear products upon orthotopic transplantation in mouse. Together, this study provides an experimental platform to study the (patho-)physiology of the lacrimal gland