Relative Depletion Research Articles

Cis-regulatory Landscape Size, Constraint, and Tissue Specificity Associate with Gene Function and Expression.

Multiple distal cis-regulatory elements (CREs) often cooperate to regulate gene expression, and the presence of multiple CREs for a gene has been proposed to provide redundancy and robustness to variation. However, we do not understand how attributes of a gene's distal CRE landscape-the CREs that contribute to its regulation-relate to its expression and function. Here, we integrate three-dimensional chromatin conformation and functional genomics data to quantify the CRE landscape composition genome-wide across ten human tissues and relate their attributes to the function, constraint, and expression patterns of genes. Within each tissue, we find that expressed genes have larger CRE landscapes than nonexpressed genes and that genes with tissue-specific CREs are more likely to have tissue-specific expression. Controlling for the association between expression level and CRE landscape size, we also find that CRE landscapes around genes under strong constraint (e.g., loss-of-function intolerant and housekeeping genes) are not significantly smaller than other expressed genes as previously proposed; however, they do have more evolutionarily conserved sequences than CREs of expressed genes overall. We also show that CRE landscape size does not associate with expression variability across individuals; nonetheless, genes with larger CRE landscapes have a relative depletion for variants that influence expression levels (expression quantitative trait loci). Overall, this work illustrates how differences in gene function, expression, and evolutionary constraint are reflected in features of CRE landscapes. Thus, considering the CRE landscape of a gene is vital for understanding gene expression dynamics across biological contexts and interpreting the effects of noncoding genetic variants.

SHARAD observations for layered ejecta deposits formed by late-Amazonian-aged impact craters at low latitudes of Mars

Frequent changes of the rotational inclination of Mars have driven global transitions of the cryosphere. Although glaciers of water ice may have extended to the equatorial region, current observations of surface deposits at latitudes lower than 30° show relative depletion in hydrogen. Thermal stability models predict that at these low latitudes, ancient water ice may be preserved below a desiccated regolith layer that is meters to hundreds of meters thick. However, confirmed detections of massive water ice and/or water ice remain sparse at low latitudes. Here we use sounding radar observations of late-Amazonian-aged impact craters with layered ejecta deposits at low latitudes to search for subsurface layering and interface properties to investigate the possible existence of subsurface water/water ice. Such craters are widespread at low latitudes, including the landing area of the Zhurong rover, Tianwen-1 mission. The layered ejecta deposits of selected craters have lateral sizes and thickness suitable for investigation by sounding radar. Compared to previously-reported, but rare, cases that contained obvious reflectors between the layered ejecta deposits and underlying materials, we detect no clear reflections in neither the layered ejecta deposits nor deeper materials, suggesting that these materials have similar dielectric properties across their interfaces. Referring to the surface permittivity of background terrains of the investigated craters, we derive a broad range of relative permittivity of ∼2–10 for materials in the layered ejecta deposits. We discuss the implications of these results in the context of past and present water ice at low latitudes of Mars.

Mechanisms of Qingyi Decoction in Severe Acute Pancreatitis-Associated Acute Lung Injury via Gut Microbiota: Targeting the Short-Chain Fatty Acids-Mediated AMPK/NF-κB/NLRP3 Pathway.

The pivotal roles of gut microbiota in severe acute pancreatitis-associated acute lung injury (SAP-ALI) are increasingly revealed, and recent discoveries in the gut-lung axis have provided potential approaches for treating SAP-ALI. Qingyi decoction (QYD), a traditional Chinese medicine (TCM), is commonly used in clinical to treat SAP-ALI. However, the underlying mechanisms remain to be fully elucidated. Herein, by using a caerulein plus lipopolysaccharide (LPS)-induced SAP-ALI mice model and antibiotics (Abx) cocktail-induced pseudogermfree mice model, we tried to uncover the roles of the gut microbiota by administration of QYD and explored its possible mechanisms. Immunohistochemical results showed that the severity of SAP-ALI and intestinal barrier functions could be affected by the relative depletion of intestinal bacteria. The composition of gut microbiota was partially recovered after QYD treatment with decreased Firmicutes/Bacteroidetes ratio and increased relative abundance in short-chain fatty acids (SCFAs)-producing bacteria. Correspondingly increased levels of SCFAs (especially propionate and butyrate) in feces, gut, serum, and lungs were observed, generally consistent with changes in microbes. Western-blot analysis and RT-qPCR results indicated that the AMPK/NF-κB/NLRP3 signaling pathway was activated after oral administration of QYD, which was found to be possibly related to the regulatory effects on SCFAs in the intestine and lungs. In conclusion, our study provides new insights into treating SAP-ALI through modulating the gut microbiota and has prospective practical value for clinical use in the future. IMPORTANCE Gut microbiota affects the severity of SAP-ALI and intestinal barrier function. During SAP, a significant increase in the relative abundance of gut pathogens (Escherichia, Enterococcus, Enterobacter, Peptostreptococcus, Helicobacter) was observed. At the same time, QYD treatment decreased pathogenic bacteria and increased the relative abundance of SCFAs-producing bacteria (Bacteroides, Roseburia, Parabacteroides, Prevotella, Akkermansia). In addition, The AMPK/NF-κB/NLRP3 pathway mediated by SCFAs along the gut-lung axis may play an essential role in preventing the pathogenesis of SAP-ALI, which allows for reduced systemic inflammation and restoration of the intestinal barrier.

Petrogenesis and tectonic implications of the early Paleozoic granites in the Lincang granitic batholith, southwestern China: Constraints from geochronology, geochemistry and Hf isotopes

This study presents the recently discovered Wulao Shan Ordovician granite within the Lincang granitic batholith, discusses its geochemical affinity, genesis, and tectonic significance, and interprets the proto-Tethys orogenic model in southwest Yunnan. LA-ICP-MS zircon U-Pb analyses indicate a crystalline age of 473.0 ± 2.9 Ma for the Wulaoshan gneissic granite. Geochemical analyses show that the Wulaoshan granite exhibits relatively high SiO2 concentrations (73.4–77.3 wt.%), strong peraluminous properties (ASI > 1.1), strongly Eu-negative anomalies, light and heavy rare earth fractionation, and relative Ba, Nb, Ta, Sr, P, and Ti depletion. SiO2 and P2O5 exhibit a strong negative correlation, whereas Rb and Y-Th with a positive correlation. The magmatic zircons have negative εHf(t) values of -5.47∼2.74. Petrographic observations and whole-rock geochemical and isotopic analyses imply no aluminum-rich minerals such as cordierite, indicating that the Wulaoshan granite is a highly fractionated, high-temperature I-type granite, which may have formed via partial melting of the magnesian-iron igneous crust. Additionally, K-feldspar, plagioclase, and biotite within the granite samples may have undergone intense fractional crystallization. The Wulao Shan gneissic granite is an arc granite associated with subduction, indicating that the Lincang Block underwent proto-Tethys subduction. This finding provides evidence for proto-Tethys subduction down to the Lincang-Simao block and further supports the bidirectional subduction model of the proto-Tethys.

Optimizing relative root-zone water depletion thresholds to maximize yield and water productivity of winter wheat using AquaCrop

Determination of relative root-zone water depletion (RRWD) thresholds to trigger irrigation is crucial to create optimal irrigation schedules targeting maximum yield and/or water productivity with limited water supply for a crop. In this study, a numerical procedure to determine RRWD thresholds was developed through coupling AquaCrop software with genetic-simplex algorithms. Using a two-year field lysimetric experiment for winter wheat conducted in the North China Plain (NCP), AquaCrop adequately simulated canopy cover, final aboveground biomass, grain yield, seasonal evapotranspiration, and soil water storage, with the normalized root mean squared error (NRMSE) smaller than 15 % and determination coefficient (R2) larger than 0.84. The global optimum range of RRWD thresholds was preliminarily determined using the genetic algorithm, and subsequently final RRWD thresholds were optimized by fine tuning using the simplex algorithm. The RRWD threshold combinations (composed of the RRWD thresholds to trigger different sequential irrigation events) for varying number of irrigation events (i.e.1–4) were optimized based on 39 years of historical meteorological data, and the effects of climate change on the optimal crop yield (Ya, opt), water productivity (WPopt), and the combinations of optimized RRWD threshold (RRWDopt) were investigated. The results indicated that both Ya, opt and WPopt generally increased with time showing a tendency of gradually elevated annual CO2 concentration and seasonal average effective temperature. Irrespective of the number of irrigation events during the winter wheat growing season, the differences of RRWDopt for different combinations of irrigation sequence and event in the same kind of hydrological year were relatively small, with a coefficient of variation consistently less than 23 % and a mean of 8 %. When combinations of mean RRWDopt were applied into AquaCrop to trigger irrigation for winter wheat in various hydrological years, the simulated yield (Ya, sim) and water productivity (WPsim) under 1–4 irrigation events were found to be comparable to their respective optimums (Ya, opt and WPopt), with all the values of Ya, sim (WPsim) falling in the range of 92 %Ya, opt (90 %WPopt). Therefore, the mean RRWDopt should be helpful to formulate rational irrigation management strategies of winter wheat under changing climatic conditions in the NCP.

Self-control, limited willpower and decision fatigue in healthcare settings.

We argue that willpower as well as its depletion may, in some circumstances, adversely impact on clinical decision-making and patient care. This psychological phenomenon has been dubbed ego depletion in social psychology. Willpower and its depletion which is known as 'ego depletion' are well-established and validated theoretical constructs in social psychology and have been studied across a range of experimental contexts. Willpower is closely related to the concept of self-control, which refers to the ability to regulate one's own behaviour and actions in order to pursue and achieve either a short- or long-term goal. We outline the clinical relevance of willpower and its depletion in relation to clinical case examples drawn from three of the authors' clinical experience with the view of developing a clinical-research agenda for future research studies. We examine willpower and its depletion in the context of three clinical case examples, which include (i) doctor-patient interactions, (ii) willpower and its depletion in relation to challenging interpersonal interactions with clinical and non-clinical work colleagues and (iii) willpower and its depletion in response to working within a challenging and unpredictable clinical environment. In contrast to the more widely recognised external resources (including space, staff allocations and night shifts), a greater understanding of how this important but under-recognised internal resource can be depleted in response to a range of different factors within clinical settings has the potential to inform and improve patient care through a renewed focus on the developing interdisciplinary clinical studies which draw upon contemporary findings from social psychology. Future work aimed at developing evidence-based interventions to help mitigate the negative impact of impaired self-control and decision fatigue within healthcare systems may in turn lead to improved patient care as well as more effective healthcare service and delivery.

Understanding the provenance and depositional conditions of Triassic sedimentary rocks from the Spiti region, Tethys Himalaya, India

The Spiti region, renowned as the Museum of Indian Geology, is a world-famous sedimentary succession containing well-exposed sequences from Neoproterozoic to Cretaceous age. In this study, Triassic siliciclastic sedimentary rocks of the Lilang Supergroup were chosen to understand weathering history, provenance, paleoclimate, and depositional conditions using a geochemical and isotopic approach. Triassic shales show more or less similar compositions with substantial enrichment in CaO compared to PAAS (Post Archean shales from Australia), which may be attributed to the association with limestones in the region. However, the sandstones display significant depletion in the trace element concentrations signifying the effect of quartz dilution. The relative depletion of mobile elements (Rb, Ba) as against immobile elements (Zr, Nb, Hf) can be noticed in the trace element spider diagram of the shales. The Triassic sedimentary rocks are characterized by enriched LREE and depleted HREE patterns with pronounced negative Eu anomalies. The Chemical Index of Alteration (CIA; 56–86) indicates low to intense chemical weathering in the source area. The unusual decrease in CIA and other weathering indices in the stratigraphically up section is attributed to changes in climate and environmental conditions during the deposition of sediments in the Triassic period. Detangling the signatures is crucial to understanding the mass extinction crisis, particularly the role of anoxia in these events. Triassic black shales represent suboxic to anoxic depositional conditions in the redox-sensitive elemental binary diagrams. The carbon isotope data of the present study is very well supported by the Total Organic Carbon (TOC), which infers that the oceanic biological system tried to recover from the depletion of biological life. The εNd and 87Sr/86Sr systematics record a shift in source terrains from the Early to Late Triassic period. The Early Triassic samples show much older depleted mantle model ages (TDM = 1.94–1.98 Ga) compared to Late Triassic sediments (TDM = 1.76–1.91 Ga). Similar interpretations can be drawn from Th/Sc ratios (from ∼ 6 to ∼ 0.05) and (La/Yb) N ratios (from ∼ 32 to ∼ 5), which record an increase in these ratios from Early Triassic to Late Triassic formations of the Spiti sedimentary rocks. Overall, trace elemental ratios and radiogenic isotopic signatures of the Triassic rocks of the Spiti region point towards Pan African granitic origin with minor impressions from the juvenile mafic-rich sources, such as Panjal Traps, the African craton, and Arabian-Nubian shield.

Titanium transport and isotopic fractionation in the Critical Zone

Stable Ti isotopes have been applied in the detrital sediment record to reconstruct the bulk composition of Earth’s continental crust due to the relationship between magmatic differentiation and Ti isotopic compositions. However, no study has systematically evaluated the influence of provenance, physical, and chemical weathering on the composition of sediments relative to the protolith they originated from. To test the influence of these processes on Ti isotopic compositions we investigate the Ti isotope composition of 82 surface samples including loess, volcaniclastic rocks, river sediment, and two separate weathering profiles through igneous rocks, collected from a broad geographical area and a range of environmental conditions. Limited but significant Ti isotope fractionation exists in samples subjected to extreme chemical weathering processes, potentially as a result of elemental mobilization. For example, the δ49Ti isotopic composition of bauxites developed on Columbia River basalt varies by up to 0.1‰, becoming isotopically heavier with increasing weathering intensity. However, negligible variation in δ49Ti was found in a second profile of saprolites developed on weathered diabase. Titanium isotope variations in loess do not correlate with chemical weathering intensity or size sorting, but may instead be related to the provenance of the sediment. We find that the δ49Ti of Amazon River sediments is correlated with the Al/Zr ratio, indicating that δ49Ti is impacted by sediment sorting. At our study sites, the river averaged offset between the isotopic composition of the bedload and the suspended sediment fraction is 0.051‰, with the largest offset being + 0.116‰. Our data suggest that during chemical weathering, heavy Ti isotopes are preferentially incorporated into secondary minerals producing higher δ49Ti in intensely weathered soils. During fluvial transport, the Ti isotopic composition of fine-grained sediment is heavier than that of its coarser counterpart. Crustal protolith composition and sorting during transport and sedimentation have a stronger effect on the Ti isotopic composition than chemical weathering. Our results have implications for studies that utilize the Ti elemental concentration to calculate relative enrichment or depletion during chemical weathering and physical transport processes in the Critical Zone and for studies using Ti isotopes in terrigenous sediments to infer the composition of their provenance.

Long-term Performance of Conductive-backed multilayered HDPE Geomembranes

The long-term performance of three multilayered textured white conductive-backed geomembranes (GMBs) is compared to the comparable textured nonconductive GMBs and their smooth edge/equivalent to investigate the effect of the conductive layer on their longevity. Oven immersion in synthetic municipal solid waste leachate is used at a range of temperatures to accelerate the ageing during an incubation period of 50 months. It is shown that the conductive layer can antagonistically or synergistically affect the antioxidant depletion of conductive-backed GMBs relative to nonconductive GMBs produced by the same GMB manufacturer and formulated using the same nominal resin and antioxidant package. However, their relative degradation at 85 °C does not necessarily follow their relative antioxidant depletion times implying that the manufacturing process and the interaction between the additive packages of these GMBs can affect their relative degradation beyond the antioxidant depletion stage. Arrhenius modelling predicts the antioxidant depletion stage at field temperatures ranging between 180 and 1400 years at 20 °C for two different conductive-backed GMBs produced by two different manufacturers. With such variation in the long-term performance of conductive-backed GMBs currently available in the market, their durability should be investigated before their use in barrier systems to ensure they can meet the required design life of the desired geoenvironmental application.

Analysis of Hydrochemical Characteristics and Causes of Drinking Water Sources in South China: A Case Study in Zhanjiang City

The evaluation of groundwater environmental quality and the identification of recharge sources are very important for groundwater utilization. In this study, hydrochemistry and isotope analysis methods are used to investigate the recharge sources and hydrochemical processes of groundwater in Zhanjiang City. The results show that all samples of groundwater were drawn on the left of the global meteoric water line (GMWL: δD = 8δ18O + 10) and local meteorological water lines (LMWL1: δD = 8.17δ18O + 11.74 and LMWL2: δD = 7.50δ18O + 6.18), indicating that the groundwater was mainly recharged by meteoric precipitation and influenced by the effect of evaporation. In the middle and deep confined aquifers, the isotope data depleted with the depth, indicating that there is a relatively weak hydraulic connection between them. In addition, compared with unconfined groundwater, the isotope data of confined groundwater showed relative depletion, indicating that the confined aquifer may be partially recharged from other confined aquifers. The main chemical types in the groundwater were Na*Ca-HCO3. There are three major natural hydrochemical processes controlling the source of groundwater ions: silicate weathering, carbonate dissolution, and the cation exchange reaction. In addition, the differences in physical and chemical properties between unconfined groundwater and confined groundwater are significant. Due to the differences in anthropogenic activities and land-use types, the nitrate of the unconfined groundwater exceeds the groundwater standards. Due to the geological background of Zhanjiang City, iron and manganese exceed the third standard of groundwater in confined groundwater. Due to groundwater exploitation, TDS levels in confined groundwater have been increasing. Closed groundwater extraction is not sustainable, and it is depleting ancient water reserves. This study highlights the effectiveness of hydrochemistry and isotope analysis methods for identifying the recharge area and recharge mode of groundwater, andit is significant for fully understanding groundwater hydrochemistry and scientifically managing and protecting groundwater.

Temporal transformation of indium speciation in rice paddy soils and spatial distribution of indium in rice rhizosphere

Indium is a potentially toxic element that could enter human food chains, including soil-rice systems. The submerged environment in rice paddy soil results in temporal and spatial variations in the chemical properties of the rice rhizosphere and bulk soils, expected to cause changes in indium's chemical speciation and consequently affect its bioavailability. Therefore, this study aimed to investigate indium speciation and fractionation in soils at different periods of rice growth under continuous submergence using X-ray absorption spectroscopy and a sequential extraction method. The predominant indium species were identified as indium-associated Fe hydroxide, and indium hydroxide and phosphate precipitates. The reductive dissolution of indium-associated Fe hydroxides led to the release of indium into the soil solution under continuous submergence of soils, and the released indium concentration decreased with time due to re-sorption and re-precipitation. Meanwhile, indium hydroxide was found to be the predominant species in rice rhizosphere using μ-X-ray absorption spectroscopy. The relative depletion of indium-associated Fe hydroxides in the rice rhizosphere was attributed to the low mobility of indium from bulk soil to rice rhizosphere and the root uptake of indium associated with Fe hydroxide around rice roots. Consequently, indium uptake by rice roots was lower during the reproductive and grain-ripening stage of rice growth. Understanding the behavior of indium will help develop a strategy to minimize uptake into crops in indium-contaminated paddy soils.

Vaginal and neonatal microbiota in pregnant women with preterm premature rupture of membranes and consecutive early onset neonatal sepsis

BackgroundPreterm premature rupture of membranes (PPROM), which is associated with vaginal dysbiosis, is responsible for up to one-third of all preterm births. Consecutive ascending colonization, infection, and inflammation may lead to relevant neonatal morbidity including early-onset neonatal sepsis (EONS). The present study aims to assess the vaginal microbial composition of PPROM patients and its development under standard antibiotic therapy and to evaluate the usefulness of the vaginal microbiota for the prediction of EONS. It moreover aims to decipher neonatal microbiota at birth as possible mirror of the in utero microbiota.MethodsAs part of the PEONS prospective multicenter cohort study, 78 women with PPROM and their 89 neonates were recruited. Maternal vaginal and neonatal pharyngeal, rectal, umbilical cord blood, and meconium microbiota were analyzed by 16S rRNA gene sequencing. Significant differences between the sample groups were evaluated using permutational multivariate analysis of variance and differently distributed taxa by the Mann–Whitney test. Potential biomarkers for the prediction of EONS were analyzed using the MetaboAnalyst platform.ResultsVaginal microbiota at admission after PPROM were dominated by Lactobacillus spp. Standard antibiotic treatment triggers significant changes in microbial community (relative depletion of Lactobacillus spp. and relative enrichment of Ureaplasma parvum) accompanied by an increase in bacterial diversity, evenness and richness. The neonatal microbiota showed a heterogeneous microbial composition where meconium samples were characterized by specific taxa enriched in this niche. The vaginal microbiota at birth was shown to have the potential to predict EONS with Escherichia/Shigella and Facklamia as risk taxa and Anaerococcus obesiensis and Campylobacter ureolyticus as protective taxa. EONS cases could also be predicted at a reasonable rate from neonatal meconium communities with the protective taxa Bifidobacterium longum, Agathobacter rectale, and S. epidermidis as features.ConclusionsVaginal and neonatal microbiota analysis by 16S rRNA gene sequencing after PPROM may form the basis of individualized risk assessment for consecutive EONS. Further studies on extended cohorts are necessary to evaluate how far this technique may in future close a diagnostic gap to optimize and personalize the clinical management of PPROM patients.Trial registrationNCT03819192, ClinicalTrials.gov. Registered on January 28, 2019.

Abstract PD1-06: Black patients with triple negative breast cancer (TNBC) have enriched stromal tumor infiltrating lymphocytes (sTILs) and receive preferential benefit from neoadjuvant immunotherapy

Abstract Introduction TNBC is overrepresented in Black women, and Black patients with TNBC have worse clinical outcomes compared to non-Black patients. This disparity likely results from racial differences in clinical, biological, and demographic features of TNBC and social determinants of health. Neoadjuvant chemoimmunotherapy is current standard of care for high-risk TNBC. However, Black patients have been poorly represented in immunotherapy TNBC trials, making it difficult to assess comparative efficacy of immunotherapy in Black patients. Methods We utilized two TNBC neoadjuvant trials to assess racial differences in the tumor immune microenvironment composition and evaluate impact of race on response to chemotherapy vs chemoimmunotherapy. NeoSTOP trial (NCT02413320) randomized 100 stage I-III TNBC patients to receive neoadjuvant carboplatin/paclitaxel + doxorubicin/cyclophosphamide (CbP+AC) or carboplatin/docetaxel (CbD). NeoPACT trial (NCT03639948) enrolled 120 patients with stage I-III TNBC who received neoadjuvant CbD + pembrolizumab (CbD+P). sTILs were centrally quantified, and RNA extracted from pretreatment tissue was subjected to next-generation sequencing. Relative leukocyte fractions were computed by CIBERSORTx. Factors were tested as predictors of pathologic complete response (pCR) using logistic regression analysis. Event-free survival (EFS) was estimated by the Kaplan-Meier method and compared between groups by log-rank test, followed by Cox regression analysis. Results The study population includes 197 patients with known race, sTILs, and gene expression data (84 patients from NeoSTOP, 113 from NeoPACT). 15/84 (18%) patients in NeoSTOP and 20/113 (18%) patients in NeoPACT self-reported Black race. There was no significant difference in age, T or N stage, or germline BRCA1/2 mutation status by race in either study. Black patients had significantly higher sTILs than non-Black patients (median 40% vs 15%, P=0.048) and were more likely to have ≥20% sTILs than non-Black patients (66% vs 44%, P=0.026). There was no significant difference in pCR by race in NeoSTOP (OR=0.60, 95% CI 0.19-1.84, P=0.37; pCR 47% for Black vs 59% for non-Black). In contrast, in NeoPACT, Black patients had a significantly higher pCR compared to non-Black patients (OR=3.27, 95% CI 1.01-10.64, P=0.049; pCR 79% for Black vs 53% for non-Black). In NeoSTOP, EFS was similar for Black and non-Black patients (3-year EFS 92% and 94%, respectively, HR=0.88, 95% CI 0.11-7.28, P=0.90). In NeoPACT, EFS was numerically higher in Black vs non-Black patients (3-year EFS 93% and 81%, respectively, HR=0.43, 95% CI 0.05-3.36, P=0.40); NeoPACT survival follow-up is ongoing at the time of this report. On CIBERSORTx analysis, Black patients had relative depletion of immunosuppressive pro-tumorigenic M2 macrophages (P=0.005) and CD4+ memory resting T cells (P=0.021) compared to non-Black patients. Conclusions Compared to non-Black patients, Black patients with TNBC are more likely to have immune-enriched tumors with lower relative abundance of immunosuppressive leukocytes. These findings suggest potential for higher relative magnitude of benefit from checkpoint inhibitor therapy in Black compared to non-Black patients. Supporting this biological hypothesis, we noted that Black and non-Black patients had equivalent rates of pCR with neoadjuvant chemotherapy; however, pCR rate among Black patients was significantly higher than in non-Black patients when treated with neoadjuvant chemoimmunotherapy. These findings should be confirmed in other studies and can optimize utilization of neoadjuvant chemoimmunotherapy. Our findings also underscore the importance of efforts to address disparity in access and use of immunotherapy in Black patients. Citation Format: Shane R. Stecklein, Rachel Yoder, Roberto Salgado, Joshua M. Staley, Anne O’Dea, Lauren Nye, Manana Elia, Deepti Satelli, Gregory Crane, Richard McKittrick, Andrew K. Godwin, Qamar Khan, Priyanka Sharma. Black patients with triple negative breast cancer (TNBC) have enriched stromal tumor infiltrating lymphocytes (sTILs) and receive preferential benefit from neoadjuvant immunotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD1-06.

Re-defining the Gut Heart Axis: A Systematic Review of the Literature on the Role of Gut Microbial Dysbiosis in Patients With Heart Failure.

Heart failure (HF) contributes to the cardiovascular health burden worldwide. Patients with heart failure have been recently studied to possess unique changes in the gut microbiome that affect immune homeostasis and metabolism. In this systematic review of the literature, we aim to identify the impact of gut dysbiosis on heart failure. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelinesto conduct our systematic review. We searched the literature on databases such as PubMed, PubMed Central (PMC), Medline, and ScienceDirect. Ten articles were included for review.There were significant differences in the gut microbiome composition in heart failure. Relative abundance of Ruminococcus gnavus, Escherichia Shigella, Streptococcus sp, Veillonella sp, and Actinobacteria, and relative depletion of Eubacterium, Prevotella, Faecalibacterium, SMB53, and Megamonas. The composition varied according to age, heart failure stage, and decompensation level. The composition remained unaltered with ejection fraction. There was an increased expression of genes responsible for the metabolism of amino acids, carbohydrates, choline trimethylamine-lyase (TMA-lyase), lipopolysaccharide (LPS) biosynthesis, tryptophan, and lipid metabolism. The resultant changes affected the levels of metabolites, such as trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), and LPS, and inflammatory markers in the feces and plasma, which contributed to heart failure. These biomarkers of heart failure could serve as targets for the prevention and treatment of heart failure. Patients with heart failure harbor a unique constellation of gut microbiota that affect the pathogenesis of heart failure. Further studies are needed to understand the causal relationship between dysbiosis and heart failure.

Self consistent grain depletions and abundances II: Effects on strong-line diagnostics of extragalactic H ii regions

ABSTRACT The depletion of elements onto dust grains is characterized using a generalized depletion strength F* for any sightline, and trend-line parameters AX, BX, and zX. The parameters AX, BX, and zX define the relative depletion pattern, for which values are published in previous works. The present study uses these parameters to calculate post-depleted gas-phase abundances of 15 different elements while varying F* from 0 to 1. An analysis of emergent strong spectral line intensities, obtained by inputting the calculated abundances into a cloudy model, shows that the depletion strength has a non-trivial effect on predicted emission lines and the thermal balance of the ionized cloud. The amount by which elements deplete also affects the coolant abundances in the gas. Furthermore, it was found that each of the parameters – metallicity, ionization parameter U, and depletion strength F* have degenerate effects on the emission-line strengths, and thermal balance of the interstellar medium (ISM). Finally, comparing our results to a sample of H ii regions using data obtained from the Mapping Nearby Galaxies at Apache Point Observatory survey (MaNGA) revealed that the best-fit F* was approximately 0.5. However, this best-fitting value does not work well for all metallicities. Removing the sulfur depletion and changing the nitrogen abundance pattern can improve the fit. As a result, extra observational evidence is required to verify the choices of parameters and better constrain the typical depletion strength in galaxies.

DOP01 The effect of vedolizumab on CD8 T cell repertoire homogeneity and blood-gut trafficking in patients with inflammatory bowel disease

Abstract Background Inflammatory bowel disease (IBD) causes T cell to infiltrate intestinal mucosa, but the heterogeneity of these cells is not understood at a clonal level. The anti-integrin α4β7 agent vedolizumab is believed to treat IBD by blocking this T cell infiltration from blood. Methods To understand the clonal distribution of T cells in IBD and how this is affected by vedolizumab, we studyined the T cell receptor (TCR) repertoire in CD8+ T cell subsets sorted from blood samples and colon mucosal biopsies via FACS. Inflamed or uninflamed colon segments from 15 ulcerative colitis and 13 Crohn’s disease patients were compared to colon biopsies from 11 people without IBD. In peripheral blood, we profiled purified α4β7+, α4β7- effector/memory, CD45RA+ terminal effector/memory (TEMRA) CD8 T cells, and mucosal-associated invariant T (MAIT) cells. In a separate cohort of 13 IBD patients, samples were obtained before and during vedolizumab therapy to determine its effect on the diversity and overlap of the TCR repertoires of blood and colon CD8+ T cells. Results CD8 TCR diversity in the mucosa and peripheral blood did not correlate with inflammation. CD8 TCR repertoire overlap between any two anatomically distinct locations of a person’s colon was consistently high, though often lower between inflamed and uninflamed sites. Repertoire overlap was also seen between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells and the lowest for MAIT cells. Inflamed tissue overlapped more than uninflamed with each blood subpopulation. Vedolizumab did not affect the overlap between colon CD8+ T cells and circulating α4β7+ CD8 T cells, nor their TCR diversity, regardless of treatment efficacy. Indeed, flow cytometry revealed no relative depletion of effector/memory T cells in the colons of vedolizumab recipients. Instead, vedolizumab caused the depletion of rare naïve mucosal T cells and dendritic cells (DC) from the colonic mucosa. Conclusion CD8 T cell clones are spread homogenously throughout the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar diversity of TCRs in both argues against local clonal expansion being the main source of excess T cells in inflamed mucosa. Rather, our data reveal increased TCR overlap between blood and inflamed mucosa to support the significance of T cell trafficking in IBD pathogenesis, particularly concerning experienced α4β7+ T cell populations. However, we surprisingly found neither gross nor clonal evidence that blockade of this trafficking is the mechanism by which vedolizumab treats IBD, instead finding only naïve T cells and DC to be depleted from the colonic mucosa in response to vedolizumab.

THE EFFECT OF VEDOLIZUMAB ON CD8 T CELL REPERTOIRE HOMOGENEITY AND BLOOD-GUT TRAFFICKING IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND Inflammatory bowel disease (IBD) causes T cell infiltration of the intestinal mucosa, but the heterogeneity of these cells is not understood at a clonal level. The drug vedolizumab is believed to treat IBD by blocking the entry of circulating integrin α4β7+ T cells into the intestinal mucosa. METHODS We sought to understand the clonal distribution of T cells in IBD and how this is affected by vedolizumab by studying the T cell receptor (TCR) repertoire in CD8+ T cell subsets sorted from blood samples and colon mucosal biopsies via FACS. Inflamed or uninflamed colon segments from 15 ulcerative colitis and 13 Crohn’s disease patients were compared to colon biopsies from 11 people without IBD. In peripheral blood, we profiled purified α4β7+, α4β7- effector/memory, CD45RA+ terminal effector/memory (TEMRA) CD8 T cells, and mucosal-associated invariant T (MAIT) cells. In a separate cohort of 13 IBD patients, samples were obtained before and during vedolizumab therapy to determine its effect on the diversity and overlap of the TCR repertoires of blood and colon CD8+ T cells. RESULTS CD8 TCR diversity in the mucosa and peripheral blood did not correlate with inflammation. Repertoire overlap between any two anatomically distinct locations of a person’s colon was consistently high, though often lower between inflamed and uninflamed sites. CD8 TCR repertoire overlap was also seen between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells and the lowest for MAIT cells. Inflamed tissue overlapped more than uninflamed with each blood subpopulation. Surprisingly, vedolizumab did not affect the degree of overlap between colon CD8+ T cells and circulating α4β7+ CD8 T cells, nor their TCR diversity, regardless of treatment efficacy. Indeed, flow cytometry revealed no relative depletion of effector/memory T cells in the colons of vedolizumab recipients. Instead, vedolizumab caused the depletion of rare naïve mucosal T cells and dendritic cells (DC) from the colonic mucosa. CONCLUSIONS CD8 T cell clones are spread homogenously throughout the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar diversity of TCRs in both argues against local clonal expansion being the main source of excess T cells in inflamed mucosa. Rather, our data reveal increased TCR overlap between blood and inflamed mucosa to support the significance of T cell trafficking in IBD pathogenesis, particularly concerning experienced α4β7+ T cell populations. However, we surprisingly found neither gross nor clonal evidence that blockade of this trafficking is the mechanism by which vedolizumab treats IBD, instead finding only naïve T cells and DC to be depleted from the colonic mucosa in response to vedolizumab.

Rare Earth Element Deposits in Mongolia

In Mongolia, rare earth element (REE) mineralization of economic significance is related either to the Mesozoic carbonatites or to the Paleozoic peralkaline granitoid rocks. Carbonatites occur as part of alkaline silicate-carbonatite complexes, which are composed mainly of nepheline syenites and equivalent volcanic rocks. The complexes were emplaced in the Gobi-Tien Shan rift zone in southern Mongolia where carbonatites usually form dikes, plugs or intruded into brecciated rocks. In mineralized carbonatites, REE occur mainly as fluorocarbonates (bastnäsite, synchysite, parisite) and apatite. Apatite is also present in the carbonatite-hosted apatite-magnetite (mostly altered to hematite) bodies. Alkaline silicate rocks and carbonatites show common geochemical features such as enrichment of light REE but relative depletion of Ti, Zr, Nb, Ta and Hf and similar Sr and Nd isotopic characteristics suggesting the involvement of the heterogeneous lithospheric mantle in the formation of both carbonatites and associated silicate rocks. Hydrothermal fluids of magmatic origin played an important role in the genesis of the carbonatite-hosted REE deposits. The REE mineralization associated with peralkaline felsic rocks (peralkaline granites, syenites and pegmatites) mainly occurs in Mongolian Altai in northwestern Mongolia. The mineralization is largely hosted in accessory minerals (mainly elpidite, monazite, xenotime, fluorocarbonates), which can reach percentage levels in mineralized zones. These rocks are the results of protracted fractional crystallization of the magma that led to an enrichment of REE, especially in the late stages of magma evolution. The primary magmatic mineralization was overprinted (remobilized and enriched) by late magmatic to hydrothermal fluids. The mineralization associated with peralkaline granitic rocks also contains significant concentrations of Zr, Nb, Th and U. There are promising occurrences of both types of rare earth mineralization in Mongolia and at present, three of them have already established significant economic potential. They are mineralization related to Mesozoic Mushgai Khudag and Khotgor carbonatites in southern Mongolia and to the Devonian Khalzan Buregtei peralkaline granites in northwestern Mongolia.

Effects of Fasting on Intermediary Metabolism Enzymes in the Liver and Muscle of Rainbow Trout

Fish can go through periods of feed deprivation, either due to natural causes influenced by temperature or management techniques in animal production, affecting their energy metabolism differently, depending on the duration of fasting in days and water temperature. This study showed the effect of different days of fasting before slaughter in rainbow trout by analyzing the intermediary metabolic enzymes in the muscle and liver. For this purpose, a non-fasting group was compared with trout that fasted for 5, 10, and 20 days (55, 107, and 200 degree days (°C d), respectively). A first phase of increased activity of enzymes involved in glycolysis was observed, increasing hexokinase enzyme activity in muscle and pyruvate kinase enzyme activity in muscle and liver. As the fasting days progressed, enzymes involved in the gluconeogenic and glycogenolytic pathways in the liver such as lactate dehydrogenase and glycogen phosphorylase increased their activity regarding the no fasted group. After 20 days of fasting (200 °C d), lipogenic and protein related enzyme activity depletion was observed, leading to significant changes in energy metabolism. Therefore, prolonged fasting with high degree days duration may compromise the energy supply for the vital development of rainbow trout.

Targeting cellular metabolism in cholangiocarcinoma with dithiazanine iodide

Background: Cholangiocarcinoma is a rare, aggressive cancer of the biliary tree which accounts for 10-20% of periampullary cancers. Therapy for cholangiocarcinoma is challenging, as this cancer is extremely resistant to standard chemotherapy regimens which act through the induction of DNA damage. The cholangiocarcinoma microenvironment is relatively hypovascular and as such, is characterized by relative hypoxia and nutrient depletion. We therefore hypothesized that metabolic inhibitors, targeting mitochondrial function might be a useful adjunct for cholangiocarcinoma treatment. We assessed the potential of the previously FDA-approved anti-parasitic compound, Dithiazanine Iodide (CDI), as an anti-cancer drug in in-vitro cell cultures of patient-derived cholangiocarcinoma cell lines and we have shown here that CDI is a strong, targeted mitochondrial inhibitor.