ABSTRACT
We present measurements of the redshift-dependent clustering of a DESI-like luminous red galaxy (LRG) sample selected from the Legacy Survey imaging data set, and use the halo occupation ...distribution (HOD) framework to fit the clustering signal. The photometric LRG sample in this study contains 2.7 million objects over the redshift range of 0.4 < z < 0.9 over 5655 deg2. We have developed new photometric redshift (photo-z) estimates using the Legacy Survey DECam and WISE photometry, with σNMAD = 0.02 precision for LRGs. We compute the projected correlation function using new methods that maximize signal-to-noise ratio while incorporating redshift uncertainties. We present a novel algorithm for dividing irregular survey geometries into equal-area patches for jackknife resampling. For a five-parameter HOD model fit using the MultiDark halo catalogue, we find that there is little evolution in HOD parameters except at the highest redshifts. The inferred large-scale structure bias is largely consistent with constant clustering amplitude over time. In an appendix, we explore limitations of Markov chain Monte Carlo fitting using stochastic likelihood estimates resulting from applying HOD methods to N-body catalogues, and present a new technique for finding best-fitting parameters in this situation. Accompanying this paper, we have released the Photometric Redshifts for the Legacy Surveys catalogue of photo-z’s obtained by applying the methods used in this work to the full Legacy Survey Data Release 8 data set. This catalogue provides accurate photometric redshifts for objects with z < 21 over more than 16 000 deg2 of sky.
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations ...affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.
Obesity is associated with consumption of energy-dense diets and development of systemic inflammation. Gut microbiota play a role in energy harvest and inflammation and can influence the change from ...lean to obese phenotypes. The nucleus of the solitary tract (NTS) is a brain target for gastrointestinal signals modulating satiety and alterations in gut-brain vagal pathway may promote overeating and obesity. Therefore, we tested the hypothesis that high-fat diet‑induced changes in gut microbiota alter vagal gut-brain communication associated with increased body fat accumulation. Sprague-Dawley rats consumed a low energy‑dense rodent diet (LFD; 3.1 kcal/g) or high energy‑dense diet (HFD, 5.24 kcal/g). Minocycline was used to manipulate gut microbiota composition. 16S Sequencing was used to determine microbiota composition. Immunofluorescence against IB4 and Iba1 was used to determine NTS reorganization and microglia activation. Nodose ganglia from LFD rats were isolated and co-cultured with different bacteria strains to determine neurotoxicity. HFD altered gut microbiota with increases in Firmicutes/Bacteriodetes ratio and in pro-inflammatory Proteobacteria proliferation. HFD triggered reorganization of vagal afferents and microglia activation in the NTS, associated with weight gain. Minocycline-treated HFD rats exhibited microbiota profile comparable to LFD animals. Minocycline suppressed HFD‑induced reorganization of vagal afferents and microglia activation in the NTS, and reduced body fat accumulation. Proteobacteria isolated from cecum of HFD rats were toxic to vagal afferent neurons in culture. Our findings show that diet‑induced shift in gut microbiome may disrupt vagal gut‑brain communication resulting in microglia activation and increased body fat accumulation.
Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful ...for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
Abstract
BACKGROUND
Evolving requirements for patient and physician safety and rapid regulatory changes have stimulated interest in neurosurgical telemedicine in the COVID-19 era.
OBJECTIVE
To ...conduct a systematic literature review investigating treatment of neurosurgical patients via telemedicine, and to evaluate barriers and challenges. Additionally, we review recent regulatory changes that affect telemedicine in neurosurgery, and our institution's initial experience.
METHODS
A systematic review was performed including all studies investigating success regarding treatment of neurosurgical patients via telemedicine. We reviewed our department's outpatient clinic billing records after telemedicine was implemented from 3/23/2020 to 4/6/2020 and reviewed modifier 95 inclusion to determine the number of face-to-face and telemedicine visits, as well as breakdown of weekly telemedicine clinic visits by subspecialty.
RESULTS
A total of 52 studies (25 prospective and 27 retrospective) with 45 801 patients were analyzed. A total of 13 studies were conducted in the United States and 39 in foreign countries. Patient management was successful via telemedicine in 99.6% of cases. Telemedicine visits failed in 162 cases, 81.5% of which were due to technology failure, and 18.5% of which were due to patients requiring further face-to-face evaluation or treatment. A total of 16 studies compared telemedicine encounters to alternative patient encounter mediums; telemedicine was equivalent or superior in 15 studies. From 3/23/2020 to 4/6/2020, our department had 122 telemedicine visits (65.9%) and 63 face-to-face visits (34.1%). About 94.3% of telemedicine visits were billed using face-to-face procedural codes.
CONCLUSION
Neurosurgical telemedicine encounters appear promising in resource-scarce times, such as during global pandemics.
Severe Early Childhood Caries (S-ECC) affects the health and well-being of young children. There is limited research in this area, though evidence suggests that children with S-ECC are at an ...increased risk of malnutrition. The purpose of this study was to determine the association between vitamin D (25(OH)D) levels and S-ECC.
This case-control study was conducted from 2009 to 2011 in the city of Winnipeg, Manitoba, Canada. 144 preschool children with S-ECC were recruited from a local health centre on the day of their slated dental surgery under general anesthetic. 122 caries-free controls were recruited from the community. Children underwent a blood draw for vitamin D (25(OH)D), calcium, parathyroid hormone, and albumin levels. Parents completed an interviewed questionnaire assessing the child's nutritional habits, oral health, and family demographics. Analyses included descriptive and bivariate statistics as well as multiple and logistic regression. A p value ≤ 0.05 was significant.
The mean age of participants was 40.8 ± 14.1 months. Children with S-ECC had significantly lower mean 25(OH)D (68.9 ± 28.0 nmol/L vs. 82.9 ± 31.1, p < 0.001), calcium (p < 0.001), and albumin (p < 0.001) levels, and significantly higher parathyroid hormone (p < 0.001) levels than those caries-free. Children with S-ECC were significantly more likely to have vitamin D levels below recognized thresholds for optimal and adequate status (i.e. < 75 and < 50 nmol/L, respectively). Multiple regression analysis revealed that S-ECC, infrequent milk consumption, and winter season were significantly associated with lower 25(OH)D concentrations. Low 25(OH)D levels, low household income, and poorer ratings of the child's general health were significantly associated with S-ECC on logistic regression.
Children with S-ECC appear to have relatively poor nutritional health compared to caries-free controls, and were significantly more likely to have low vitamin D, calcium, and albumin concentrations and elevated PTH levels.
Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In
mice, we examined the ...impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin,
mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with
mice on ad libitum feeding, changes in the microbiome of the
mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in
on IF but not in
on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.
Selective vascular access to the brain is desirable in metabolic tracer, pharmacological and other studies aimed to characterize neural properties in isolation from somatic influences from chest, ...abdomen or limbs. However, current methods for artificial control of cerebral circulation can abolish pulsatility-dependent vascular signaling or neural network phenomena such as the electrocorticogram even while preserving individual neuronal activity. Thus, we set out to mechanically render cerebral hemodynamics fully regulable to replicate or modify native pig brain perfusion. To this end, blood flow to the head was surgically separated from the systemic circulation and full extracorporeal pulsatile circulatory control (EPCC) was delivered via a modified aorta or brachiocephalic artery. This control relied on a computerized algorithm that maintained, for several hours, blood pressure, flow and pulsatility at near-native values individually measured before EPCC. Continuous electrocorticography and brain depth electrode recordings were used to evaluate brain activity relative to the standard offered by awake human electrocorticography. Under EPCC, this activity remained unaltered or minimally perturbed compared to the native circulation state, as did cerebral oxygenation, pressure, temperature and microscopic structure. Thus, our approach enables the study of neural activity and its circulatory manipulation in independence of most of the rest of the organism.
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