Tele-Operated Lunar Rover Navigation Using Lidar

Near real-time tele-operated driving on the lunar surface remains constrained by bandwidth and signal latency despite the Moon s relative proximity. As part of our work within NASA s Human-Robotic Systems Project (HRS), we have developed a stand-alone modular LIDAR based safeguarded tele-operation system of hardware, middleware, navigation software and user interface. The system has been installed and tested on two distinct NASA rovers-JSC s Centaur2 lunar rover prototype and ARC s KRex research rover- and tested over several kilometers of tele-operated driving at average sustained speeds of 0.15 - 0.25 m/s around rocks, slopes and simulated lunar craters using a deliberately constrained telemetry link. The navigation system builds onboard terrain and hazard maps, returning highest priority sections to the off-board operator as permitted by bandwidth availability. It also analyzes hazard maps onboard and can stop the vehicle prior to contacting hazards. It is robust to severe pose errors and uses a novel scan alignment algorithm to compensate for attitude and elevation errors

Infants with esophageal atresia and right aortic arch: Characteristics and outcomes from the Midwest Pediatric Surgery Consortium

Purpose Right sided aortic arch (RAA) is a rare anatomic finding in infants with esophageal atresia with or without tracheoesophageal fistula (EA/TEF). In the presence of RAA, significant controversy exists regarding optimal side for thoracotomy in repair of the EA/TEF. The purpose of this study was to characterize the incidence, demographics, surgical approach, and outcomes of patients with RAA and EA/TEF. Methods A multi-institutional, IRB approved, retrospective cohort study of infants with EA/TEF treated at 11 children's hospitals in the United States over a 5-year period (2009 to 2014) was performed. All patients had a minimum of one-year follow-up. Results In a cohort of 396 infants with esophageal atresia, 20 (5%) had RAA, with 18 having EA with a distal TEF and 2 with pure EA. Compared to infants with left sided arch (LAA), RAA infants had a lower median birth weight, (1.96 kg (IQR 1.54–2.65) vs. 2.57 kg (2.00–3.03), p = 0.01), earlier gestational age (34.5 weeks (IQR 32–37) vs. 37 weeks (35–39), p = 0.01), and a higher incidence of congenital heart disease (90% vs. 32%, p  0.29). Conclusion RAA in infants with EA/TEF is rare with an incidence of 5%. Compared to infants with EA/TEF and LAA, infants with EA/TEF and RAA are more severely ill with lower birth weight and higher rates of prematurity and complex congenital heart disease. In neonates with RAA, surgical repair of the EA/TEF is technically feasible via thoracotomy from either chest. A higher incidence of anastomotic strictures may occur with a right-sided approach

Mammalian Otolin: A Multimeric Glycoprotein Specific to the Inner Ear that Interacts with Otoconial Matrix Protein Otoconin-90 and Cerebellin-1

The mammalian otoconial membrane is a dense extracellular matrix containing bio-mineralized otoconia. This structure provides the mechanical stimulus necessary for hair cells of the vestibular maculae to respond to linear accelerations and gravity. In teleosts, Otolin is required for the proper anchoring of otolith crystals to the sensory maculae. Otoconia detachment and subsequent entrapment in the semicircular canals can result in benign paroxysmal positional vertigo (BPPV), a common form of vertigo for which the molecular basis is unknown. Several cDNAs encoding protein components of the mammalian otoconia and otoconial membrane have recently been identified, and mutations in these genes result in abnormal otoconia formation and balance deficits.Here we describe the cloning and characterization of mammalian Otolin, a protein constituent of otoconia and the otoconial membrane. Otolin is a secreted glycoprotein of ∼70 kDa, with a C-terminal globular domain that is homologous to the immune complement C1q, and contains extensive posttranslational modifications including hydroxylated prolines and glycosylated lysines. Like all C1q/TNF family members, Otolin multimerizes into higher order oligomeric complexes. The expression of otolin mRNA is restricted to the inner ear, and immunohistochemical analysis identified Otolin protein in support cells of the vestibular maculae and semi-circular canal cristae. Additionally, Otolin forms protein complexes with Cerebellin-1 and Otoconin-90, two protein constituents of the otoconia, when expressed in vitro. Otolin was also found in subsets of support cells and non-sensory cells of the cochlea, suggesting that Otolin is also a component of the tectorial membrane.Given the importance of Otolin in lower organisms, the molecular cloning and biochemical characterization of the mammalian Otolin protein may lead to a better understanding of otoconial development and vestibular dysfunction

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

The Role of Nuclear Receptors in Tissue-Specific Gene Expression: The Impact of Genetic Variation on DNA Binding

Nuclear receptors (NRs) are ligand-sensitive transcription factors that regulate a wide array of biological processes including development, metabolism, and circadian rhythms. All NRs share a common protein structure, including highly conserved DNA binding domains and a highly variable N-terminal A/B domain, and are very popular drug targets. To better understand the role of alternative A/B domains between NR isoforms and the impact of genetic variation on gene expression in the liver, we employed two experimental approaches. The NR hepatocyte nuclear factor 4α (HNF4α), a master regulator of liver-specific gene expression, is regulated by two promoters (P1 and P2) in the liver resulting in proteins with different A/B domains. P1-HNF4α is expressed in fetal and normal adult liver while P2-HNF4α is expressed only in the fetal liver and in liver cancer. We compared wildtype mice, which express only HNF4α1 (P1) in the adult liver, to exon-swap mice that express only HNF4α7 (P2) for global changes in gene expression (RNA-seq), chromatin binding (ChIP-seq), and unique protein interactions (RIME). The results show that P1- and P2-HNF4α isoforms differentially regulate hundreds of transcripts in the adult liver, including the NR CAR (Nr1i3), and may be recruited differentially to non-HNF4α binding sites by unique protein interactions. They also exhibit altered metabolic pathways, especially cytochrome P450 (Cyp) genes. All told, the results show that changes in just 16-30 amino acids in the AF-1 region of an NR can have profound effects on gene expression. Utilizing protein binding microarrays (PBM), we can measure the DNA binding affinity of a given NR against both alleles of 125,000 genetic variants in a single experiment to probe for affinity altering SNPs (aaSNPs). By mining SNPs from ChIP-seq peaks and eQTLs from the GTEx project, we have identified thousands of aaSNPs, hundreds of which show significant correlation to changes in gene expression within their regulatory network. Analysis of aaSNPs from GWAS studies associated with Alzheimer’s disease identified a large number of genetic variants that can alter the DNA binding affinity of PPARɣ in the APOE locus. Additionally, we show the power of the PBMs to validate many aaSNPs derived from in vivo analysis and suggest a role for the PBM technology in characterizing how genetic diversity may play a role in personalized medicine

The Role of Nuclear Receptors in Tissue-Specific Gene Expression: The Impact of Genetic Variation on DNA Binding

Nuclear receptors (NRs) are ligand-sensitive transcription factors that regulate a wide array of biological processes including development, metabolism, and circadian rhythms. All NRs share a common protein structure, including highly conserved DNA binding domains and a highly variable N-terminal A/B domain, and are very popular drug targets. To better understand the role of alternative A/B domains between NR isoforms and the impact of genetic variation on gene expression in the liver, we employed two experimental approaches. The NR hepatocyte nuclear factor 4α (HNF4α), a master regulator of liver-specific gene expression, is regulated by two promoters (P1 and P2) in the liver resulting in proteins with different A/B domains. P1-HNF4α is expressed in fetal and normal adult liver while P2-HNF4α is expressed only in the fetal liver and in liver cancer. We compared wildtype mice, which express only HNF4α1 (P1) in the adult liver, to exon-swap mice that express only HNF4α7 (P2) for global changes in gene expression (RNA-seq), chromatin binding (ChIP-seq), and unique protein interactions (RIME). The results show that P1- and P2-HNF4α isoforms differentially regulate hundreds of transcripts in the adult liver, including the NR CAR (Nr1i3), and may be recruited differentially to non-HNF4α binding sites by unique protein interactions. They also exhibit altered metabolic pathways, especially cytochrome P450 (Cyp) genes. All told, the results show that changes in just 16-30 amino acids in the AF-1 region of an NR can have profound effects on gene expression. Utilizing protein binding microarrays (PBM), we can measure the DNA binding affinity of a given NR against both alleles of 125,000 genetic variants in a single experiment to probe for affinity altering SNPs (aaSNPs). By mining SNPs from ChIP-seq peaks and eQTLs from the GTEx project, we have identified thousands of aaSNPs, hundreds of which show significant correlation to changes in gene expression within their regulatory network. Analysis of aaSNPs from GWAS studies associated with Alzheimer’s disease identified a large number of genetic variants that can alter the DNA binding affinity of PPARɣ in the APOE locus. Additionally, we show the power of the PBMs to validate many aaSNPs derived from in vivo analysis and suggest a role for the PBM technology in characterizing how genetic diversity may play a role in personalized medicine

Identification of Alternatively Spliced Genes in Metabolic Disease Pathways

As of 2022, one-third of US adults experience metabolic diseases. Current therapies treat symptoms but do not address disruptions in signaling pathways of the liver that lead to the development of metabolic diseases. It is now recognized that many genes involved in metabolic disease pathways are alternatively spliced. This research aims to identify real alternative splicing events at genes that can serve as therapeutic targets. Alternative splicing is a critical process by which exons within pre-mRNA are either in- cluded or removed to generate diverse mRNAs and proteins. Transcriptomic data from the livers of both male and female mice under several different conditions–fed versus fasted, wildtype, and ɑ7HMZ mice were analyzed for splicing events using an RNA- seq program, DEXSeq. ɑ7HMZ mice express an alternative form of the transcription factor HNF4a, a critical liver and metabolism regulator. Current RNA-seq programs cannot distinguish alternative splicing from other activity occurring at the gene locus, so manual curation is necessary. Using a curation criterion, I manually analyzed 177 genes identified by the program for alternative splicing events. My analysis identified splicing events at mitochondrial genes usually expressed during fasting conditions and genes whose loss-of-function is implicated in obesity, hyperglycemia, and hypertension. Future research will analyze the mechanistic roles of these mitochondrial genes in various met- abolic disease models

Impact of various high fat diets on gene expression and the microbiome across the mouse intestines

High fat diets (HFDs) have been linked to several diseases including obesity, diabetes, fatty liver, inflammatory bowel disease (IBD) and colon cancer. In this study, we examined the impact on intestinal gene expression of three isocaloric HFDs that differed only in their fatty acid composition-coconut oil (saturated fats), conventional soybean oil (polyunsaturated fats) and a genetically modified soybean oil (monounsaturated fats). Four functionally distinct segments of the mouse intestinal tract were analyzed using RNA-seq-duodenum, jejunum, terminal ileum and proximal colon. We found considerable dysregulation of genes in multiple tissues with the different diets, including those encoding nuclear receptors and genes involved in xenobiotic and drug metabolism, epithelial barrier function, IBD and colon cancer as well as genes associated with the microbiome and COVID-19. Network analysis shows that genes involved in metabolism tend to be upregulated by the HFDs while genes related to the immune system are downregulated; neurotransmitter signaling was also dysregulated by the HFDs. Genomic sequencing also revealed a microbiome altered by the HFDs. This study highlights the potential impact of different HFDs on gut health with implications for the organism as a whole and will serve as a reference for gene expression along the length of the intestines